PMID: 28751539 (None) Terms: |
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0 | Mechanisms of resistance to NTRK inhibitors and therapeutic strategies in NTRK1-rearranged cancers . | ||
1 | Neurotrophic receptor tyrosine kinase 1 ( NTRK1 ) gene rearrangement leads to constitutive activation of NTRK1 , which induces high transforming ability . | ||
2 | NTRK-rearranged cancers have been identified in several cancer types , such as glioblastoma , non-small - cell lung cancer , and colorectal cancer . | ||
3 | Although there are currently no clinically approved inhibitors that target NTRK1 , several tyrosine kinase inhibitors ( TKIs ) , such as entrectinib and LOXO-101 , are in clinical trials . | ||
4 | The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance . | ||
5 | We examined the sensitivity of TPM3-NTRK1 -transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors . | ||
6 | Μ | Acquired NTRK inhibitor -resistant mutations were screened by N-ethyl-N-nitrosourea ( ENU ) mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs . | |
7 | Μ | We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain , including G595R , and IGF1R bypass pathway mediated resistance . | |
8 | After identifying the resistance mechanisms , we performed drug screening with small-molecular inhibitors to overcome the resistance . | ||
9 | ✓ | As a result , we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants , both of which showed resistance to entrectinib or LOXO101 . | GM-ASS-SR |
10 | Furthermore , cabozantinib with an insulin growth factor receptor type 1 ( IGF1R ) inhibitor such as OSI906 could overcome bypass pathway-mediated resistance . | ||
11 | We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance . |
PMID: 28625641 (Patient) Terms: |
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0 | Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 ( G796S/R ) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib . | ||
1 | Acquired epidermal growth factor receptor ( EGFR ) resistance mutations to osimertinib are common , including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR . | ||
2 | Here we report the emergence of novel EGFR solvent front mutations at Gly796 ( G796S/R ) in addition to a hinge pocket L792F/H mutations , and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA ( ctDNA ) assay in the course of clinical care . | ||
3 | A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib . | ||
4 | The patient was initiated on osimertinib with disease shrinkage after 2 months , but tumor regrowth was observed after 5 months of osimertinib treatment . | ||
5 | Μ | Assay of plasma ctDNA at this time revealed these different secondary resistance mutations all in trans with each other including distinct mutations at the same codon producing different amino acid changes : G796S/R ( mutant allele frequency [MAF] ; 14.4% ) , C797S/G ( MAF : 2.26% ) , L792F/H ( MAF : 0.36% ) , and V802F ( MAF : 0.40% ) , in addition to the pre-existing L858R ( MAF : 179% ) and T790M ( MAF : 182% ) but all in cis with T790M . | |
6 | ✓ | The G796S/R mutations are homologous with known reported solvent front mutations in ALK G1202R , ROS1 G2032R , TrkA G595R and TrkC G623R , all of which are associated with acquired resistance to type I TKIs . | |
7 | Μ | In silico modeling revealed mutation at G796 interferes with osimertinib binding to the EGFR kinase domain at the phenyl aromatic ring position as this residue forms a narrow "hydrophobic sandwich" with L718 , while L792F/H mutation interferes with osimertinib binding at the methoxyl group on the phenyl ring . | |
8 | Multiple resistance mutations at differing allele frequencies including novel EGFR solvent front mutations can emerge in a single patient with progression on osimertinib potentially due to tumor hetereogeneity and definitely present a significant therapeutic and drug development challenge . |
PMID: 28471124 (Patient) Terms: |
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0 | Multiplex genomic test of mutation and fusion genes in small biopsy specimen of lung cancer . | ||
1 | We evaluated multiple oncogenic mutations and fusion genes in small specimen obtained by bronchoscopy . | ||
2 | Eight patients with lung cancer were recruited , 3 small cell lung cancer , 3 non-small cell lung cancer , 1 adenocarcinoma and 1 squamous cell carcinoma . | ||
3 | A median value of extracted RNA and DNA amounts from specimen was 1573 ng ( range 3675 to 8900 ) and 6700 ng ( range 550 to 68000 ng ) , respectively . | ||
4 | We applied amplicon sequencing panels that cover exon regions of 41 genes related to lung tumorigenesis as well as total 61 major variants of ALK , ROS , RET or NTRK1 fusion transcripts . | ||
5 | Μ | Nineteen of 41 gene mutations were detected in our isolated DNAs of 8 patients . | |
6 | Μ | We could detect four to eleven mutations in each specimen ; however the mutation combination in each 8 patients were different . | |
7 | Μ | The most common genetic alterations were TP53 , KMT2D , MET , NOTCH2 and SETD2 , which were detected in 4 to 6 patients . | |
8 | Μ | We did not detect fusion transcripts of ALK , ROS , RET and NTRK1 in every specimen . | |
9 | In conclusion , multiplex genomic test was performed on small amounts specimen of bronchoscopy biopsy with a 100% success rate . | ||
10 | Such testing is considered to be able to assist physicians in matching patients with approved or experimental targeted treatments . |
PMID: 28444624 (Patient) Terms: this review, clinical trial, phase I |
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0 | Targeting NTRK fusion in non-small cell lung cancer : rationale and clinical evidence . | ||
1 | In the era of personalized medicine , the identification of targetable genetic alterations represented a major step forward in anticancer therapy . | ||
2 | NTRK rearrangements represent the molecular driver of a subset of solid tumors , including 3% of non-small-cell lung cancers ( NSCLCs ) . | ||
3 | Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies . | ||
4 | The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors , touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC , which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials . |
PMID: 28428274 (Cell) Terms: , mouse models, mouse |
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0 | EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases . | ||
1 | Oncogenic kinase fusions of ALK , ROS1 , RET , and NTRK1 act as drivers in human lung and other cancers . | ||
2 | Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene -targeted therapy ultimately enables the emergence of drug -resistant clones , limiting the long-term effectiveness of these therapies . | ||
3 | To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene -addicted cancer cells , we investigated the role of EGFR signaling in drug -naive cancer cells harboring these oncogene fusions . | ||
4 | We defined three distinct roles for EGFR in the response to oncogene -specific therapies . | ||
5 | First , EGF -mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes . | ||
6 | Second , fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR . | ||
7 | Third , EGFR enabled bypass signaling to critical downstream pathways such as MAPK . | ||
8 | While evidence of EGFR -mediated bypass signaling has been reported after ALK and ROS1 blockade , our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells , mouse models , and human clinical specimens before the onset of acquired drug resistance . | ||
9 | Collectively , our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene -specific inhibitors , providing a rationale to cotarget EGFR to reduce the risks of developing drug resistance . | ||
10 | Cancer Res ; 77 ( 13 ) ; 3551-63 . | ||
11 | (c) 2017 AACR . |
PMID: 28332364 (None) Terms: |
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0 | Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells . | ||
1 | PURPOSE : | ||
2 | c-Met and its ligand , hepatocyte growth factor ( HGF ) , play a critical role in oncogenesis and metastatic progression . | ||
3 | The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 ( a c-Met receptor tyrosine kinase inhibitor ) in non-small cell lung cancer . | ||
4 | MATERIALS AND METHODS : | ||
5 | Z'-LYTE kinase assay was employed to screen the kinase enzymogram , and mechanism of action ( MOA ) analysis was used to identify the inhibited kinases . | ||
6 | Cell proliferation was then analyzed by CCK8 assay , and cell migration was determined by transwell assay . | ||
7 | The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting , respectively . | ||
8 | Finally , the secretion of HGF was detected by ELISA assay . | ||
9 | RESULTS : | ||
10 | c-Met , activated protein kinase ( AMPK ) , and tyrosine kinase A ( TRKA ) were inhibited by SIM-89 with the IC(5) (0) values of 297 nmol/L , 1.31 mumol/L , and 150.2 nmol/L , respectively . | ||
11 | SIM-89 exerted adenosine triphosphate ( ATP ) competitive inhibition on c-Met . | ||
12 | Moreover , the expressions of STAT1 , JAK1 , and c-Met in H460 cells were decreased by SIM-89 treatment , and c-Met phosphorylation was suppressed in A549 , H441 , H1299 , and B16F10 cells by the treatment . | ||
13 | In addition , SIM-89 treatment significantly decreased the level of HGF , which accounted for the activation of c-Met receptor tyrosine kinase . | ||
14 | Finally , we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment . | ||
15 | CONCLUSION : | ||
16 | In conclusion , SIM-89 inhibits tumor cell proliferation , migration and HGF autocrine , suggesting it's potential antitumor activity . |
PMID: 28254765 (None) Terms: |
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0 | Biological therapies in nonsmall cell lung cancer . | ||
1 | Biological therapies have improved survival outcomes of advanced-stage nonsmall cell lung cancer ( NSCLC ) . | ||
2 | Μ | Genotype-directed therapies have changed treatment paradigms of patients with EGFR-mutant and ALK/ROS1-rearranged lung adenocarcinomas , and the list of druggable targets with demonstrated clinical actionability ( BRAF , MET , RET , NTRK1 and HER2 ) continues to expand . | |
3 | Furthermore , we have incrementally understood the mechanisms of cancer immune evasion and foresee ways to effectively circumvent them , particularly at the immune checkpoint level . | ||
4 | Drugs targeting the tumour immune-evasive PD-1 pathway have demonstrated remarkable treatment benefits in this disease , with a non-negligible fraction of patients potentially receiving long-term survival benefits . | ||
5 | Herein , we briefly discuss the role of various medical disciplines in the management of advanced-stage NSCLC and review the most relevant biological therapies for this disease , with particular emphasis in genotype-directed therapies and immune checkpoint inhibitors . |
PMID: 28183697 (Patient) Terms: Phase I Trial |
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0 | Safety and Antitumor Activity of the Multitargeted Pan-TRK , ROS1 , and ALK Inhibitor Entrectinib : Combined Results from Two Phase I Trials ( ALKA-372-001 and STARTRK-1 ) . | ||
1 | Entrectinib , a potent oral inhibitor of the tyrosine kinases TRKA/B/C , ROS1 , and ALK , was evaluated in two phase I studies in patients with advanced or metastatic solid tumors , including patients with active central nervous system ( CNS ) disease . | ||
2 | Here , we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3 , ROS1 , or ALK gene fusions , naive to prior TKI treatment targeting the specific gene , and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose . | ||
3 | Entrectinib was well tolerated , with predominantly Grades 1/2 adverse events that were reversible with dose modification . | ||
4 | Responses were observed in non-small cell lung cancer , colorectal cancer , mammary analogue secretory carcinoma , melanoma , and renal cell carcinoma , as early as 4 weeks after starting treatment and lasting as long as >2 years . | ||
5 | Notably , a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer . | ||
6 | Significance : Gene fusions of NTRK1/2/3 , ROS1 , and ALK ( encoding TRKA/B/C , ROS1 , and ALK , respectively ) lead to constitutive activation of oncogenic pathways . | ||
7 | Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors , including in patients with primary or secondary CNS disease . | ||
8 | Cancer Discov ; 7(4) ; 400-9 . | ||
9 | (c) 2017 AACR . | ||
10 | This article is highlighted in the In This Issue feature , p. 339 . |
PMID: 28081338 (Patient) Terms: |
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0 | New immunohistochemical markers in the differential diagnosisof nonsmall cell lung carcinoma . | ||
1 | BACKGROUND/AIM : The aim of this study was to investigate Napsin-A , NTRK-1 , NTRK-2 , Desmoglein-3 , and Desmocollin-3 in the differential diagnosis and prognosis of nonsmall cell lung cancer . | ||
2 | MATERIALS AND METHODS : The expression of Napsin-A , NTRK-1 , NTRK-2 , and Desmoglein-3 was examined by immunohistochemistry in 50 squamous cell carcinomas and 50 adenocarcinomas . | ||
3 | Desmocollin-3 was investigated in 29 squamous cell carcinoma and 29 adenocarcinoma cases . | ||
4 | Associations between expression profiles of Napsin-A , NTRK-1 , NTRK-2 , Desmoglein-3 , and Desmocollin-3 in lung cancers and clinicopathological variables were analyzed . | ||
5 | RESULTS : | ||
6 | Napsin-A staining was statistically significant in detecting adenocarcinomas versus squamous cell carcinomas . | ||
7 | The sensitivity of Napsin-A for adenocarcinomas was 96% and the specificity was 100% . | ||
8 | NTRK-2 and Desmocollin-3 staining were statistically significant in detecting squamous cell carcinomas versus adenocarcinomas . | ||
9 | Desmoglein-3 , Napsin-A , and NTRK-2 had no effect on survival . | ||
10 | Disease-free survival time was significantly shorter in cases that were moderately positive with NTRK-1 . | ||
11 | CONCLUSION : | ||
12 | Our data suggest that Napsin-A , NTRK-2 , and Desmocollin-3 are useful markers in the differentiation of nonsmall cell lung cancer . |
PMID: 27912827 (None) Terms: This review, clinical trial |
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0 | New Targets in Non-Small Cell Lung Cancer . | ||
1 | With the implementation of genomic technologies into clinical practice , we have examples of the predictive benefit of targeted therapy for oncogene -addicted cancer and identified molecular dependencies in non-small cell lung cancer . | ||
2 | The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy . | ||
3 | Advances have validated oncogenic driver genes and led to the development of targeted agents . | ||
4 | This review highlights treatment options , including clinical trials for ROS1 rearrangement , RET fusions , NTRK1 fusions , MET exon skipping , BRAF mutations , and KRAS mutations . |
PMID: 27856237 (Cell) Terms: in vitro |
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0 | Synthesis , anticancer , and docking studies of salicyl-hydrazone analogues : A novel series of small potent tropomyosin receptor kinase A inhibitors . | ||
1 | A series of novel salicyl-hydrazone analogues were synthesized and evaluated for their in vitro cytotoxic activities in five human cancer cell lines , namely , lung cancer ( A549 ) , ovarian cancer ( SK-OV-3 ) , skin cancer (SK-MEL-2) , colon cancer ( HCT15 ) and pancreatic cancer ( MIA-PaCa-2 ) cells , and for their in vitro tropomyosin receptor kinase A ( TrkA ) inhibitory activities . | ||
2 | Each of the compounds showed significant cytotoxicity against all cancer cells . | ||
3 | Compound 3i was found to be most potent against all cancer cell lines with IC50 values of 2.46 ( A549 ) , 0.87 ( SK-OV-3 ) , 1.43 ( SK-MEL-2 ) , 0.89 ( HCT15 ) , and 0.48muM ( MIA-PaCa-2 ) , followed by compound 3l . | ||
4 | Cytotoxicity of 3i was similar to that of doxorubicin ( 087muM ) against HCT15 cells . | ||
5 | Compounds 3i and 3l also showed highest TrkA inhibitory activities with IC50 values of 0.231 and 0.380muM , respectively . | ||
6 | A SAR study of the series revealed that compounds with hydroxyl groups showed better cytotoxicity and TrkA inhibitory potency ( in the following order 2,4-OH>2,3,4-OH>3,4-OH>4-OH ) than compounds possessing electron donating or withdrawing groups on the benzylidenephenyl ring . | ||
7 | Μ | Docking studies of compounds 3i and 3l conducted on the crystal structure of TrkA receptor ( a promising target for anticancer agents ) showed both had a high docking score and similar order of experimental TrkA inhibitory activities . | |
8 | The formation of several hydrogen bonds involving N and O containing moieties contributed most significantly to ligand binding and stabilization at the active site of the receptor . | ||
9 | In addition , ligand - receptor complexes were further stabilized by pi-cation , pi-anion , amide-pi stacked , and van der Waal's interactions . | ||
10 | Conformational analyses showed ligand molecules adopted similar conformations at the receptor active site during interactions , but that the low energy optimized conformations of compounds 3i and 3l differed . |
PMID: 27826534 (Patient) Terms: this review |
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0 | Fusion gene and splice variant analyses in liquid biopsies of lung cancer patients . | ||
1 | Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance . | ||
2 | In contrast , a blood extraction is safe , can be performed at many time points during the course disease and encourages appropriate therapy modifications , potentially improving the patient's clinical outcome and quality of life . | ||
3 | Fusion of the tyrosine kinase genes anaplastic lymphoma kinase ( ALK ) , C-ROS oncogen 1 ( ROS 1 ) , rearranged during transfection ( RET ) and neurotrophic tyrosine kinase 1 ( NTRK1 ) occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors . | ||
4 | In addition , a MET splicing variant of exon 14 , has been reported in 2-4% of lung adenocarcinoma and recent studies suggests that targeted therapies inhibiting MET signaling would be beneficial for patients with this alteration . | ||
5 | Μ | In this review , we will summarize the new techniques recently developed to detect ALK , RET , ROS and NTRK1 fusions and MET exon 14 splicing variant in liquid biopsy using plasma , serum , circulating tumor cells ( CTCs ) , platelets and exosomes as starting material . |
PMID: 27413712 (None) Terms: clinical trial |
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0 | Tackling ALK in non-small cell lung cancer : the role of novel inhibitors . | ||
1 | Crizotinib is an oral inhibitor of anaplastic lymphoma kinase ( ALK ) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer ( NSCLC ) , accounting to its superiority compared to chemotherapy . | ||
2 | Unfortunately , virtually all ALK-rearranged tumors acquire resistance to crizotinib , frequently within one year since the treatment initiation . | ||
3 | To date , therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds . | ||
4 | Second-generation ALK inhibitors such as ceritinib ( LDK378 ) , alectinib ( CH5424802/RO5424802 ) and brigatinib ( AP26113 ) have shown relevant clinical activity , consequently fostering their rapid clinical development and their approval by health agencies . | ||
5 | The third-generation inhibitor lorlatinib ( PF-06463922 ) , selectively active against ALK and ROS1 , harbors impressive biological potency ; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials . | ||
6 | The NTRK1-3 and ROS1 inhibitor entrectinib ( RXDX-101 ) has been reported to act against NSCLC harboring ALK fusion proteins too . | ||
7 | Despite the quick development of these novel agents , several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC . | ||
8 | This position paper will discuss the development , the current evidence and approvals , as long as the future perspectives of new ALK inhibitors beyond crizotinib . | ||
9 | Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity . | ||
10 | The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective , in order to develop treatment strategies tailored on the disease evolution of every single patient . |
PMID: 27370605 (Cell) Terms: |
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0 | Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer . | ||
1 | PURPOSE : | ||
2 | Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations , such as NTRK1 and ROS1 rearrangements , are complicated by the cost and protracted timeline of drug discovery . | ||
3 | EXPERIMENTAL DESIGN : | ||
4 | In an effort to identify inhibitors of NTRK1 and ROS1 , which are aberrantly activated in some patients with non-small cell lung cancer ( NSCLC ) , we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes . | ||
5 | RESULTS : | ||
6 | This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 -transformed Ba/F3 , including the crizotinib-resistant mutants G2032R and L2026M ( IC50 = 9 , 26 , and 11 nmol/L , respectively ) . | ||
7 | Cabozantinib inhibited CD74-ROS1 -transformed Ba/F3 cells more potently than brigatinib ( wild-type/G2032R/L2026M IC50 = 30/170/200 nmol/L , respectively ) , entrectinib ( IC50 = 6/2,200/3,500 nmol/L ) , and PF-06463922 ( IC50 = 1/270/2 nmol/L ) . | ||
8 | Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines . | ||
9 | The IGF-1R inhibitor BMS-536924 potently inhibited CD74-NTRK1 -transformed compared with parental Ba/F3 cells ( IC50 = 19 nmol/L vs. >470 nmol/L ) . | ||
10 | A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response . | ||
11 | CONCLUSIONS : | ||
12 | While acquired resistance to targeted therapies is challenging , this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib . | ||
13 | Clin Cancer Res ; 23(1) ; 204-13 . | ||
14 | (c) 2016 AACR . |
PMID: 27151654 (Patient) Terms: Clinical Trial, clinical trial |
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0 | Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials . | ||
1 | BACKGROUND : | ||
2 | The National Comprehensive Cancer Network ( NCCN ) guidelines for patients with metastatic non-small cell lung cancer ( NSCLC ) recommend testing for EGFR , BRAF , ERBB2 , and MET mutations ; ALK , ROS1 , and RET rearrangements ; and MET amplification . | ||
3 | We investigated the feasibility and utility of comprehensive genomic profiling ( CGP ) , a hybrid capture-based next-generation sequencing ( NGS ) test , in clinical practice . | ||
4 | METHODS : | ||
5 | CGP was performed to a mean coverage depth of 576x on 6,832 consecutive cases of NSCLC ( 2012-2015 ) . | ||
6 | Genomic alterations ( GAs ) ( point mutations , small indels , copy number changes , and rearrangements ) involving EGFR , ALK , BRAF , ERBB2 , MET , ROS1 , RET , and KRAS were recorded . | ||
7 | We also evaluated lung adenocarcinoma ( AD ) cases without GAs , involving these eight genes . | ||
8 | RESULTS : | ||
9 | The median age of the patients was 64 years ( range : 13-88 years ) and 53% were female . | ||
10 | Among the patients studied , 4,876 ( 71% ) harbored atleast one GA involving EGFR ( 20% ) , ALK ( 41% ) , BRAF ( 57% ) , ERBB2 ( 60% ) , MET ( 56% ) , ROS1 ( 15% ) , RET ( 24% ) , or KRAS ( 32% ) . | ||
11 | In the remaining cohort of lung AD without these known drivers , 273 cancer-related genes were altered in atleast 0.1% of cases , including STK11 ( 21% ) , NF1 ( 13% ) , MYC ( 98% ) , RICTOR ( 64% ) , PIK3CA ( 54% ) , CDK4 ( 43% ) , CCND1 ( 40% ) , BRCA2 ( 25% ) , NRAS ( 23% ) , BRCA1 ( 17% ) , MAP2K1 ( 12% ) , HRAS ( 07% ) , NTRK1 ( 07% ) , and NTRK3 ( 02% ) . | ||
12 | CONCLUSION : | ||
13 | CGP is practical and facilitates implementation of the NCCN guidelines for NSCLC by enabling simultaneous detection of GAs involving all seven driver oncogenes and KRAS . | ||
14 | Μ | Furthermore , without additional tissue use or cost , CGP identifies patients with "pan-negative" lung AD who may benefit from enrollment in mechanism-driven clinical trials . | |
15 | IMPLICATIONS FOR PRACTICE : | ||
16 | National Comprehensive Cancer Network guidelines for patients with metastatic non-small cell lung cancer ( NSCLC ) recommend testing for several genomic alterations ( GAs ) . | ||
17 | The feasibility and utility of comprehensive genomic profiling were studied in NSCLC and in lung adenocarcinoma ( AD ) without GAs . | ||
18 | Of patients with NSCLC , 71% harbored atleast one GA to a gene listed in the guidelines or KRAS ; 273 cancer-related genes were altered in atleast 0.1% of the AD cases . | ||
19 | Although logistical and administrative hurdles limit the widespread use of next-generation sequencing , the data confirm the feasibility and potential utility of comprehensive genomic profiling in clinical practice . |
PMID: 26939704 (Patient) Terms: in vitro, xenograft, phase I/II, clinical trial, mice |
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0 | Entrectinib , a Pan-TRK , ROS1 , and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications . | ||
1 | Activated ALK and ROS1 tyrosine kinases , resulting from chromosomal rearrangements , occur in a subset of non-small cell lung cancers ( NSCLC ) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib , ceritinib , and alectinib . | ||
2 | More recently , low-frequency rearrangements of TRK kinases have been described in NSCLC , colorectal carcinoma , glioblastoma , and Spitzoid melanoma . | ||
3 | Entrectinib , whose discovery and preclinical characterization are reported herein , is a novel , potent inhibitor of ALK , ROS1 , and , importantly , of TRK family kinases , which shows promise for therapy of tumors bearing oncogenic forms of these proteins . | ||
4 | Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets . | ||
5 | Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors , including the TRKA -dependent colorectal carcinoma KM12 , ROS1-driven tumors , and several ALK -dependent models of different tissue origins , including a model of brain-localized lung cancer metastasis . | ||
6 | Entrectinib is currently showing great promise in phase I/II clinical trials , including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC . | ||
7 | The drug is , thus , potentially suited to the therapy of several molecularly defined cancer settings , especially that of TRK -dependent tumors , for which no approved drugs are currently available . | ||
8 | Mol Cancer Ther ; 15(4) ; 628-39 . | ||
9 | (c) 2016 AACR . |
PMID: 26881293 (None) Terms: This review, phase I, phase II |
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0 | The potential of neurotrophic tyrosine kinase ( NTRK ) inhibitors for treating lung cancer . | ||
1 | INTRODUCTION : | ||
2 | Μ | Molecular alterations in neurotrophic tyrosine kinase ( NTRK ) genes have been identified in several solid tumors including lung cancer . | |
3 | Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition , leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway , which are currently undner early clinical investigation . | ||
4 | AREA COVERED : | ||
5 | This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer . | ||
6 | It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors , which have shown very promising activity in early phase I studies . | ||
7 | EXPERT OPINION : | ||
8 | Among the several NTRK-inhibitors , entrectinib and LOXO-101 are those in more advanced stage of clinical development . | ||
9 | Both agents have shown encouraging activity along with a tolerable safety profile in patients with different solid tumors harboring NTRK-fusions , emerging as new promising therapeutic options for molecularly selected patients with advanced Trk-driven lung cancers . | ||
10 | Results from ongoing phase II basket trials are eagerly awaited . |
PMID: 26565381 (Patient) Terms: NCT02097810 |
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0 | Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer . | ||
1 | INTRODUCTION : | ||
2 | Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 ( NTRK1 ) occur in a subset of non-small cell lung cancers ( NSCLCs ) and other solid tumor malignancies , leading to expression of an oncogenic TrkA fusion protein . | ||
3 | Entrectinib ( RXDX-101 ) is an orally available tyrosine kinase inhibitor , including TrkA . | ||
4 | We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib . | ||
5 | METHODS : | ||
6 | We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction ( AMP ) . | ||
7 | A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors ( NCT02097810 ) . | ||
8 | We assessed safety and response to treatment . | ||
9 | RESULTS : | ||
10 | We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort . | ||
11 | A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib . | ||
12 | Entrectinib was well tolerated , with no grade 3-4 adverse events . | ||
13 | Within three weeks of starting on treatment , the patient reported resolution of prior dyspnea and pain . | ||
14 | Restaging CT scans demonstrated a RECIST partial response ( PR ) and complete resolution of all brain metastases . | ||
15 | This patient has continued on treatment for over 6 months with an ongoing PR . | ||
16 | CONCLUSIONS : | ||
17 | Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement , indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements , including those with central nervous system metastases . |
PMID: 26457764 (None) Terms: This review, clinical trial |
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0 | Entrectinib : a potent new TRK , ROS1 , and ALK inhibitor . | ||
1 | INTRODUCTION : | ||
2 | Receptor tyrosine kinases ( RTKs ) and their signaling pathways , control normal cellular processes ; however , their deregulation play important roles in malignant transformation . | ||
3 | In advanced non-small cell lung cancer ( NSCLC ) , the recognition of oncogenic activation of specific RTKs , has led to the development of molecularly targeted agents that only benefit roughly 20% of patients . | ||
4 | Entrectinib is a pan-TRK , ROS1 and ALK inhibitor that has shown potent anti-neoplastic activity and tolerability in various neoplastic conditions , particularly NSCLC . | ||
5 | AREAS COVERED : | ||
6 | This review outlines the pharmacokinetics , pharmacodynamics , mechanism of action , safety , tolerability , pre-clinical studies and clinical trials of entrectinib , a promising novel agent for the treatment of advanced solid tumors with molecular alterations of Trk-A , B and C , ROS1 or ALK . | ||
7 | EXPERT OPINION : | ||
8 | Among the several experimental drugs under clinical development , entrectinib is emerging as an innovative and promising targeted agent . | ||
9 | The encouraging antitumor activity reported in the Phase 1 studies , together with the acceptable toxicity profile , suggest that entrectinib , thanks to its peculiar mechanism of action , could play an important role in the treatment-strategies of multiple TRK-A , B , C , ROS1 , and ALK - dependent solid tumors , including NSCLC and colorectal cancer . | ||
10 | That being said , further evidence for its clinical use is still needed . |
PMID: 26420428 (Patient) Terms: prospective, CLINICAL TRIAL, Clinical Trial |
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0 | Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer . | ||
1 | BACKGROUND : | ||
2 | The clinical implementation of genomic profiling for lung cancer with high-throughput , multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients . | ||
3 | Μ | We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer . | |
4 | PATIENTS AND METHODS : | ||
5 | We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK , RET , ROS1 , and NTRK1 fusion transcripts . | ||
6 | We then determined the proportion of patients who received genotype-directed therapy and their overall survival ( OS ) . | ||
7 | RESULTS : | ||
8 | Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed . | ||
9 | The most common genetic alterations were TP53 mutations in 42 patients , followed by EGFR mutations in 25 , STK11 mutations in 12 , and KRAS mutations in 10 . | ||
10 | Μ | Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma . | |
11 | ✓ | The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy ( median OS not achieved ) was significantly longer than that of those with no mutation ( 181 months , P = 0041 ) or of those with a mutation not so treated ( 61 months , P = 00027 ) . | RO-ASS-GM |
12 | CONCLUSIONS : | ||
13 | Multiplex genomic testing was performed on formalin-fixed , paraffin-embedded tumor specimens with a success rate of >/ = 95% . | ||
14 | Such testing can assist physicians in matching patients with approved or experimental targeted treatments . | ||
15 | CLINICAL TRIAL REGISTRATION : | ||
16 | The University Medical Hospital Information Network ( UMIN ) Clinical Trials Registry under the identifier UMIN000014782 . |
PMID: 26200269 (Patient) Terms: |
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0 | Unique Genetic and Survival Characteristics of Invasive Mucinous Adenocarcinoma of the Lung . | ||
1 | INTRODUCTION : | ||
2 | Invasive mucinous adenocarcinoma is a unique histologic subtype of lung cancer , and our knowledge of its genetic and clinical characteristics is rapidly evolving . | ||
3 | Here , we present next - generation sequencing analysis of nucleotide variant and fusion events along with clinical follow-up in a series of lung mucinous adenocarcinoma . | ||
4 | METHODS : | ||
5 | We collected 72 mucinous adenocarcinomas from the United States and Korea . | ||
6 | All had been previously assessed for KRAS and EGFR mutations . | ||
7 | For KRAS wild-type cases ( n = 30 ) , we performed deep targeted next-generation sequencing for gene fusions and nucleotide variants and correlated survival and other clinical features . | ||
8 | RESULTS : | ||
9 | Μ | As expected , KRAS mutations were the most common alteration found ( 63% of cases ) ; however , the distribution of nucleotide position alterations was more similar to that observed in gastrointestinal tumors than other lung tumors . | |
10 | Μ | Within the KRAS-negative cases , we found numerous potentially targetable gene fusions and mutations , including CD74-NRG1 , VAMP2-NRG1 , TRIM4-BRAF , TPM3-NTRK1 , and EML4-ALK gene fusions and ERBB2 , BRAF , and PIK3CA mutations . | |
11 | Μ | Unexpectedly , we found only two cases with TP53 mutation , which is much lower than observed in lung adenocarcinomas in general . | |
12 | The overall mutation burden was low in histologically confirmed mucinous adenocarcinomas from the public The Cancer Genome Atlas exome data set , regardless of smoking history , suggesting a link between TP53 status and mutation burden in mucinous tumors . | ||
13 | There was no significant difference for recurrence-free survival between stage-matched mucinous and nonmucinous adenocarcinomas . | ||
14 | It was notable that all recurrence sites were in the lungs for completely resected cases . | ||
15 | CONCLUSIONS : | ||
16 | Our data suggest that mucinous adenocarcinoma is typified by (1) frequent KRAS mutations and a growing list of gene fusions , but rare TP53 mutations , (2) a low mutation burden overall , and (3) a recurrence-free survival similar to stage-matched nonmucinous tumors , with recurrences limited to the lungs . |
PMID: 26001971 (Patient) Terms: |
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0 | Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma . | ||
1 | Chromosomal rearrangements of the NTRK1 gene , which encodes the high affinity nerve growth factor receptor ( tropomyosin related kinase , TRKA ) , have been observed in several epithelial cancers , such as colon cancer , papillary thyroid carcinoma or non small cell lung cancer . | ||
2 | The various NTRK1 fusions described so far lead to constitutive activation of TRKA kinase activity and are oncogenic . | ||
3 | We further investigated here the existence and the frequency of NTRK1 gene rearrangements in colorectal cancer . | ||
4 | Using immunohistochemistry and quantitative reverse transcriptase PCR , we analyzed a series of human colorectal cancers . | ||
5 | Μ | We identified two TRKA positive cases over 408 , with NTRK1 chromosomal rearrangements . | |
6 | Μ | One of these rearrangements is a TPM3-NTRK1 fusion already observed in colon cancer , while the second one is a TPR-NTRK1 fusion never described in this type of cancer . | |
7 | These findings further confirm that translocations in the NTRK1 gene are recurring events in colorectal cancer , although occurring at a low frequency ( around 05% ) . |
PMID: 25888090 (None) Terms: |
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0 | Novel ALK inhibitors in clinical use and development . | ||
1 | Somatic LKB1 mutations promote cervical cancer progression . |
PMID: 25870798 (None) Terms: in vivo, in vitro, clinical trial, mouse ) models, mouse |
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0 | Beyond ALK-RET , ROS1 and other oncogene fusions in lung cancer . | ||
1 | Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer ( NSCLC ) lacking activating EGFR , KRAS , ALK , BRAF , or HER2 oncogene aberrations . | ||
2 | Μ | RET and ROS1 fusion-positive tumors are mainly observed in young , female , and/or never smoking patients . | |
3 | Studies based on in vitro and in vivo ( i.e. , mouse ) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy . | ||
4 | Accordingly , there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors ( TKIs ) against RET and ROS1 proteins in patients with fusion-positive lung cancer . | ||
5 | Other gene fusions ( NTRK1 , NRG1 , and FGFR1/2/3 ) that are targetable by existing TKIs have also been identified in NSCLCs . | ||
6 | Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions . |
PMID: 25723109 (Patient) Terms: |
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0 | Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement . | ||
1 | Approximately 50% of conventional inflammatory myofibroblastic tumors ( IMTs ) harbor ALK gene rearrangement and overexpress ALK . | ||
2 | Recently , gene fusions involving other kinases have been implicated in the pathogenesis of IMT , including ROS1 and in 1 patient PDGFRB . | ||
3 | However , it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT . | ||
4 | In this study , we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations . | ||
5 | Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies . | ||
6 | The lack of ALK immunoreactivity was not an excluding factor . | ||
7 | As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer , we set out to evaluate abnormalities in ALK , ROS1 , PDGFRB , NTRK1 , and RET by fluorescence in situ hybridization . | ||
8 | In addition , next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases , which identified EML4-ALK fusions in 2 cases . | ||
9 | Of the 62 IMTs ( 25 children and 37 adults ) , 35 ( 56% ) showed ALK gene rearrangement . | ||
10 | Of note , EML4-ALK inversion was noted in 7 ( 20% ) cases , seen mainly in the lung and soft tissue of young children including 2 lesions from newborns . | ||
11 | Μ | There were 6 ( 10% ) ROS1-rearranged IMTs , all except 1 presenting in children , mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes , often positive for ROS1 immunohistochemistry . | |
12 | Two of the cases showed TFG-ROS1 fusions . | ||
13 | Interestingly , 1 adult IMT revealed a RET gene rearrangement , a previously unreported finding . | ||
14 | Our results show that 42/62 ( 68% ) IMTs are characterized by kinase fusions , offering a rationale for targeted therapeutic strategies . | ||
15 | Interestingly , 90% of fusion-negative IMTs were seen in adults , whereas >90% of pediatric IMT showed gene rearrangements . | ||
16 | EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT , closely recapitulating the pattern seen in lung cancer . |
PMID: 25512530 (None) Terms: |
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0 | Genetic modifiers of EGFR dependence in non-small cell lung cancer . | ||
1 | Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor ( EGFR ) represent a common molecular subset of non-small cell lung cancer ( NSCLC ) cases . | ||
2 | ✓ | EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors ( TKIs ) and thus represent a dependency in NSCLCs harboring these alterations , but the genetic basis of EGFR dependence is not fully understood . | |
3 | Here , we applied an unbiased , ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells . | ||
4 | This approach identified 18 kinase and kinase -related genes whose overexpression can substitute for EGFR in EGFR -dependent PC9 cells , and these genes include seven of nine Src family kinase genes , FGFR1 , FGFR2 , ITK , NTRK1 , NTRK2 , MOS , MST1R , and RAF1 . | ||
5 | A subset of these genes can complement loss of EGFR activity across multiple EGFR -dependent models . | ||
6 | Unbiased gene -expression profiling of cells overexpressing EGFR bypass genes , together with targeted validation studies , reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase ( PI3K ) -AKT pathways . | ||
7 | Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes . | ||
8 | Together , these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival . |
PMID: 25505733 (None) Terms: Clinical Trial |
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0 | Promising Targets and Current Clinical Trials in Metastatic Non-Squamous NSCLC . | ||
1 | Lung adenocarcinoma is the most common subtype of lung cancer today . | ||
2 | With the discovery of epidermal growth factor receptor ( EGFR ) mutations , anaplastic lymphoma kinase ( ALK ) rearrangements , and effective targeted therapy , personalized medicine has become a reality for patients with lung adenocarcinoma . | ||
3 | Here , we review potential additional targets and novel therapies of interest in lung adenocarcinoma including targets within the cell surface ( receptor tyrosine kinases EGFR , human epidermal growth factor receptor 2 , RET , ROS1 , mesenchymal-epidermal transition , TRK ) , targets in intracellular signal transduction ( ALK , RAS-RAF-MEK , PI3K-AKT-PTEN , WNT ) , nuclear targets such as poly-ADP ribose polymerase , heat shock protein 90 , and histone deacetylase , and selected pathways in the tumor environment . | ||
4 | With the evolving ability to identify specific molecular aberrations in patient tumors in routine practice , our ability to further personalize therapy in lung adenocarcinoma is rapidly expanding . |
PMID: 25384085 (Patient) Terms: |
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0 | Anchored multiplex PCR for targeted next-generation sequencing . | ||
1 | We describe a rapid target enrichment method for next-generation sequencing , termed anchored multiplex PCR ( AMP ) , that is compatible with low nucleic acid input from formalin-fixed paraffin-embedded ( FFPE ) specimens . | ||
2 | AMP is effective in detecting gene rearrangements ( without prior knowledge of the fusion partners ) , single nucleotide variants , insertions , deletions and copy number changes . | ||
3 | Validation of a gene rearrangement panel using 319 FFPE samples showed 100% sensitivity ( 95% confidence limit : 96.5-100% ) and 100% specificity ( 95% confidence limit : 99.3-100% ) compared with reference assays . | ||
4 | On the basis of our experience with performing AMP on 986 clinical FFPE samples , we show its potential as both a robust clinical assay and a powerful discovery tool , which we used to identify new therapeutically important gene fusions : ARHGEF2-NTRK1 and CHTOP-NTRK1 in glioblastoma , MSN-ROS1 , TRIM4-BRAF , VAMP2-NRG1 , TPM3-NTRK1 and RUFY2-RET in lung cancer , FGFR2-CREB5 in cholangiocarcinoma and PPL-NTRK1 in thyroid carcinoma . | ||
5 | AMP is a scalable and efficient next-generation sequencing target enrichment method for research and clinical applications . |
PMID: 25054037 (Patient) Terms: in vitro, In vitro |
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0 | Investigation of neurotrophic tyrosine kinase receptor 1 fusions and neurotrophic tyrosine kinase receptor family expression in non-small - cell lung cancer and sensitivity to AZD7451 in vitro . | ||
1 | Advances in the molecular segmentation of lung cancer has raised the possibility that neurotrophic tyrosine kinase receptor ( NTRK ) 1 fusions and NTRK1-3 expression may be promising molecular targets for future therapeutic interventions . | ||
2 | We investigated the antitumor effects of a selective pan-NTRK inhibitor , AZD7451 , by evaluating its antiproliferative effects on the KM12 cell line ( a colorectal cancer cell line harboring a tropomyosin-NTRK1 fusion ) and the H460 and H810 cell lines [large-cell neuroendocrine carcinoma ( LCNEC ) cell lines expressing NTRK2] . | ||
3 | Relative quantitative polymerase chain reaction ( qPCR ) was performed to measure the mRNA levels of the NTRK1-3 tyrosine kinase domain using cDNA extracted from KM12 , H460 and H810 cells . | ||
4 | The cultures were grown in 6-well plates at a density of 1.0x106 cell/well and treated with AZD7451 at different doses ( 1 , 25 , 4 , 5 , 75 and 10 nM ) using dimethyl sulfoxide as a control . | ||
5 | Following a 24-h incubation , the number of surviving cells was measured using a hemocytometer . | ||
6 | Furthermore , we performed western blotting of the high-affinity nerve growth factor receptor (TRKA) and NTRK2 (TRKB) proteins and monitored the effects on the downstream signaling pathways Akt and ERK in these cell lines following treatment with AZD7451 ( KM12 and H460 : 0 , 1 and 5 nM ; H810 : 0 and 5 nM ) . | ||
7 | Immunohistochemical analyses of the surgically resected samples were also performed , using anti-NTRK1,2 antibodies . | ||
8 | We performed reverse-transcription PCR and direct sequencing to investigate NTRK fusions in 268 patients ; however , were unable to confirm the presence of NTRK fusions in this cohort . | ||
9 | Further immunohistochemical analyses of the primary patient samples demonstrated that none of 61 tumors had NTRK1 overexpression and 7 of 39 samples exhibited NTRK2 expression , including 1 LCNEC sample . | ||
10 | Μ | The qPCR results from the KM12 cell line revealed an apparent increase and overexpression of NTRK1 mRNA levels , while H460 cells exhibited a modest increase and the H810 cell line showed no apparent increase in the expression of any NTRK1-3 isoforms . | |
11 | There were no increases in the NTRK2 mRNA levels in any of the three cell lines , although KM12 and H460 cells exhibited low levels of NTRK2 expression . | ||
12 | Μ | In vitro growth and proliferation of the KM12 cell line harboring the NTRK1-fusion was found to be potently inhibited by AZD7451 at a concentration of 2 nM . | |
13 | The proliferation of H460 cells was also found to be inhibited at a concentration of 5 nM , while there was no apparent inhibitory effect of AZD7451 on the growth or proliferation of H810 cells . | ||
14 | Western blotting of KM12 cells treated with AZD7451 also revealed a potent inhibition of TRKA phosphorylation following AZD7451 treatment . | ||
15 | Analysis of H460 cells confirmed the expression and inhibition of phosphorylation of NTRK2 , whereas there was little to no expression of TRKA/B in H810 cells . | ||
16 | Subsequent in vitro analysis of cell lines treated with the pan-TRK inhibitor AZD7451 suggested that the proliferation of KM12 and H460 cells was significantly inhibited by AZD7451 , while H810 cells expressing low levels of wild-type NTRK1-3 were not inhibited . | ||
17 | Based on these results , there is potential for a NTRK -dependent proliferation driver in a subpopulation of lung cancer patients with NTRK expression . | ||
18 | In addition , pharmacological inhibition with a NTRK inhibitor , such as AZD7451 , in cells harboring NTRK1 fusions , may be associated with beneficial antitumor effects . |
PMID: 24857124 (None) Terms: clinical trial |
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0 | Management and future directions in non-small cell lung cancer with known activating mutations . | ||
1 | Lung cancer accounts for a quarter of all cancer deaths . | ||
2 | Non-small cell lung cancer ( NSCLC ) is currently segregated by the presence of actionable driver oncogenes . | ||
3 | This review will provide an overview of molecular subsets of lung cancer , including descriptions of the defining oncogenes ( EGFR , ALK , KRAS , ROS1 , RET , BRAF , ERBB2 , NTRK1 , FGFR , among others ) and how these predict for response to small molecule tyrosine kinase inhibitors ( TKIs ) that are either clinically available or in clinical trial development for advanced NSCLC . | ||
4 | Particular focus will be placed on subsets with EGFR mutated and ALK rearranged NSCLC . | ||
5 | Somatic TKI-sensitizing EGFR mutations ( such as exon 19 deletions and L858R substitutions ) are the most robust predictive biomarker for symptom improvement , radiographic response , and increment in progression-free survival ( PFS ) when EGFR TKIs ( gefitinib , erlotinib , and afatinib ) are used for patients with advanced NSCLC . | ||
6 | However , the palliative benefits that EGFR TKIs afford are limited by multiple biologic mechanisms of tumor adaptation/resistance ( such as the EGFR-T790M mutation and oncogene bypass tracks ) , and future efforts toward delaying , preventing , and treating resistance are underway . | ||
7 | Similar to EGFR mutations , ALK rearrangements exemplify an oncogene -driven NSCLC that can be effectively palliated with a precision TKI therapy ( the multitargeted ALK/MET/ROS1 TKI crizotinib ) . | ||
8 | When resistance to first - line crizotinib therapy occurs , multiple second generation ALK TKIs have demonstrated impressive rates of disease control in clinical trials , and these may modify long-term outcomes for patients with ALK-positive NSCLC . | ||
9 | The development of TKIs for other oncogene -driven NSCLCs may expand the portfolio of precision therapies for this recalcitrant cancer . |
PMID: 24809946 (None) Terms: |
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0 | Tropomyosin receptor kinase inhibitors : a patent update 2009 - 2013 . | ||
1 | INTRODUCTION : | ||
2 | Tropomyosin receptor kinases ( Trks ) are a family of three similar tyrosine kinases activated by peptide hormones of the neurotrophin family . | ||
3 | The nerve growth factor antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA pathway in pain . | ||
4 | As an alternative modality , small-molecule inhibitors of the Trks have been pursued in recent years to probe the role of these neurotrophin pathways in pain , cancer and other indications . | ||
5 | AREAS COVERED : | ||
6 | This paper reviews the patent literature between mid-2009 and 2013 , claiming inhibitors of Trk family members as the primary biological targets . | ||
7 | Μ | Additional patents have been reviewed where Trk is not the main kinase of interest but in which high Trk potency is observed and the chemical matter is particularly noteworthy . | |
8 | Patents pre-dating this period have been reviewed previously . | ||
9 | Scifinder and Google were used to find relevant patents and clinical information using Trk or Tropomyosin as the search term . | ||
10 | EXPERT OPINION : | ||
11 | Considerable recent progress has been made in the identification of selective pan Trk inhibitors with pharmacodynamic and pharmacokinetic properties appropriate for clinical evaluation . | ||
12 | Inhibitors of both active and inactive conformations of the Trks as well as peripherally restricted molecules have been identified . | ||
13 | Furthermore , TrkA-selective allosteric inhibitors have recently been disclosed , which enables the biology of this isoform to be probed . | ||
14 | The recent identification of a TrkA gene fusion in a subset of lung cancer patients will increase further the attraction of Trk inhibition to the pharmaceutical industry . |
PMID: 24744988 (Patient) Terms: in vitro |
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0 | Will the Requirement by the US FDA to Simultaneously Co-Develop Companion Diagnostics ( CDx ) Delay the Approval of Receptor Tyrosine Kinase Inhibitors for RTK-Rearranged ( ROS1- , RET- , AXL- , PDGFR-alpha- , NTRK1- ) Non-Small Cell Lung Cancer Globally ? | ||
1 | The discovery of anaplastic lymphoma kinase ( ALK ) rearrangement in non-small cell lung cancer ( NSCLC ) in 2007 and the approval of crizotinib for the treatment of advanced ALK-rearranged NSCLC in 2011 represents a landmark in the development of targeted oncology therapy . | ||
2 | The approval of crizotinib was accompanied simultaneously by the approval of the Vysis ( Abbott Molecular ) break-apart fluorescence in situ hybridization ( FISH ) test as the companion diagnostic ( CDx ) test to detect ALK rearrangement . | ||
3 | Pfizer , the manufacturer of crizotinib , sponsored the screening of thousands of patients and the standardization of the ALK FISH test as part of the approval process for crizotinib , a first in class ALK inhibitor . | ||
4 | Many pharmaceutical companies are now using the Food and Drug Administration ( FDA )- approved ALK FISH assay to enroll patients onto trials for their own respective ALK inhibitors . | ||
5 | In essence they are "piggybacking" on the FDA-approved ALK FISH assay without having to pay for the development of a CDx , nor screening for ALK-rearranged NSCLC patients in the protocols because screening for ALK rearrangement is now the standard of care in NSCLC after the approval of crizotinib . | ||
6 | Since 2007 , rearrangement in more receptor tyrosine kinases ( RTKs ) such as ROS1 , RET , AXL , PDGFR-alpha , and NTRK1 have been discovered in NSCLC but the incidence of each subtype of RTK-rearranged NSCLC is quite rare . | ||
7 | Crizotinib has now demonstrated significant clinical activity in ROS1-rearranged NSCLC patients . | ||
8 | Whether crizotinib will gain official FDA approval for use in ROS1-rearranged NSCLC , on the other hand , remains unclear as there is no test for ROS1-rearrangement currently being developed to support US FDA approval as a CDx . | ||
9 | This may be due in part to the fact that the full cost associated with the development of a pre-market approved-approved CDx must be borne by the company seeking the first drug approval in a new indication . | ||
10 | Given the low incidence of ROS1-rearrangement in NSCLC , and the availability of crizotinib in most countries , a more cost-effective way is for crizotinib to gain compendium listing for ROS1-rearranged NSCLC in treatment guidelines . | ||
11 | However , without a formal indication from the FDA , a drug cannot be marketed for off label use , it is unlikely that payers public or private will routinely pay for molecular testing for ROS1-rearrangement in NSCLC let alone reimburse off label use of crizotinib . | ||
12 | Similarly , several marketed tyrosine kinase inhibitors ( TKIs ) in the US ( sorafenib , sunitinib , vandetanib , cabozantinib , regorafenib ) are potent RET inhibitors in vitro . | ||
13 | It does not make sense for any one pharmaceutical company to shoulder the full cost of developing a particular CDx for RET-rearranged NSCLC where , once approved , it may be used by other pharmaceutical companies to gain addition labeling approval for their own RET inhibitors . | ||
14 | Thus , the requirement by the US FDA that a specific CDx have to be co-developed and standardized for each of the molecular subtype of NSCLC as part of the drug approval process , while prudent , may have the un-intended consequence of deterring clinical development of these TKIs in these very rare molecular subsets of NSCLC . | ||
15 | While we all march to the drumbeat of precision cancer medicine , the stringent requirement of co-development CDx for each molecular subtype of solid tumor may inadvertently make this goal substantially more difficult to achieve . |
PMID: 24736082 (None) Terms: |
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0 | A novel fusion of TPR and ALK in lung adenocarcinoma . | ||
1 | INTRODUCTION : | ||
2 | Anaplastic lymphoma kinase ( ALK ) fusion is the most common mechanism for overexpression and activation in non-small - cell lung carcinoma . | ||
3 | Several fusion partners of ALK have been reported , including echinoderm microtubule-associated protein -like 4 , TRK-fused gene , kinesin family member 5B , kinesin light chain 1 ( KLC1 ) , protein tyrosine phosphatase and nonreceptor type 3 , and huntingtin interacting protein 1 ( HIP1 ) . | ||
4 | METHODS AND RESULTS : | ||
5 | A 60-year-old Korean man had a lung mass which was a poorly differentiated adenocarcinoma with ALK overexpression . | ||
6 | Μ | By using an Anchored Multiplex polymerase chain reaction assay and sequencing , we found that tumor had a novel translocated promoter region ( TPR ) -ALK fusion . | |
7 | The fusion transcript was generated from an intact , in-frame fusion of TPR exon 15 and ALK exon 20 ( t ( 1 ; 2 ) ( q31.1 ; p23 ) ) . | ||
8 | The TPR-ALK fusion encodes a predicted protein of 1192 amino acids with a coiled-coil domain encoded by the 5'-2 of the TPR and juxtamembrane and kinase domains encoded by the 3'-end of the ALK . | ||
9 | CONCLUSIONS : | ||
10 | The novel fusion gene and its protein TRP-ALK , harboring coiled-coil and kinase domains , could possess transforming potential and responses to treatment with ALK inhibitors . | ||
11 | This case is the first report of TPR-ALK fusion transcript in clinical tumor samples and could provide a novel diagnostic and therapeutic candidate target for patients with cancer , including non-small - cell lung carcinoma . |
PMID: 24162815 (None) Terms: |
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0 | Oncogenic and drug -sensitive NTRK1 rearrangements in lung cancer . | ||
1 | We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein) . | ||
2 | Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic . | ||
3 | Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth . | ||
4 | Μ | Tumor samples from 3 of 91 patients with lung cancer ( 33% ) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions . |
PMID: 23656788 (None) Terms: ex vivo |
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0 | TrkB is responsible for EMT transition in malignant pleural effusions derived cultures from adenocarcinoma of the lung . | ||
1 | Lung cancer is the leading cause of cancer-related mortality worldwide . | ||
2 | Recent evidence indicates that tumors contain a subpopulation of cancer stem cells ( CSCs ) that are responsible for tumor maintenance and spread . | ||
3 | CSCs have recently been linked to the occurrence of epithelial-to-mesenchymal transition ( EMT ) . | ||
4 | Neurotrophins ( NTs ) are growth factors that regulate the biology of embryonic stem cells and cancer cells , but still little is known about the role NTs in the progression of lung cancer . | ||
5 | In this work , we investigated the role of the NTs and their receptors using as a study system primary cell cultures derived from malignant pleural effusions ( MPEs ) of patients with adenocarcinoma of the lung . | ||
6 | We assessed the expression of NTs and their receptors in MPE-derived adherent cultures vs.spheroids enriched in CSC markers . | ||
7 | Μ | We observed in spheroids a selectively enhanced expression of TrkB , both at the mRNA and protein levels . | |
8 | Both K252a , a known inhibitor of Trk activity , and a siRNA against TrkB strongly affected spheroid morphology , induced anoikis and decreased spheroid forming efficiency . | ||
9 | Treatment with neurotrophins reversed the inhibitory effect of K252a . | ||
10 | Importantly , TrkB inhibition caused loss of vimentin expression as well as that of a set of transcription factors known to be linked to EMT . | ||
11 | These ex vivo results nicely correlated with an inverse relationship between TrkB and E-cadherin expression measured by immunohistochemistry in a panel of lung adenocarcinoma samples . | ||
12 | We conclude that TrkB is involved in full acquisition of EMT in lung cancer , and that its inhibition results in a less aggressive phenotype . |
PMID: 22948297 (Cell) Terms: In vivo, xenograft, mice, tumor growth of NSCLC xenografts |
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0 | Antitumor activity of AZ64 via G2/M arrest in non-small cell lung cancer . | ||
1 | AZ64 is a novel antitumor agent designed as a tropomyosin-related kinase ( Trk ) inhibitor ; however , its effect on lung cancer and its mechanism of action remain unclear . | ||
2 | This study aimed to elucidate the antitumor activity of AZ64 and its mechanism of action against non-small cell lung cancer ( NSCLC ) . | ||
3 | Our results demonstrate that AZ64 has a potent anti-proliferative effect on NSCLC cells and acts in a dose - and time -dependent manner . | ||
4 | We also demonstrate that AZ64 suppresses the anchorage -independent growth and invasion of NSCLC cells . | ||
5 | In vivo experiments demonstrated that AZ64 significantly reduced the tumor growth of NSCLC xenografts in nude mice and was well-tolerated . | ||
6 | Mechanistic experiments revealed that AZ64 induced the G2/M arrest of NSCLC cells by the accumulation of phospho-cdc2 (Tyr15) at the G2/M transition , following the downregulation of Cdc25C expression . | ||
7 | Collectively , our data demonstrate that AZ64 is a potential antitumor drug that may be used for the treatment of NSCLC , which functions by targeting the G2/M transition via the inhibition of the dephosphorylation of phospho-cdc2 (Tyr15) . |
PMID: 22050016 (None) Terms: Phase I-II trial |
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0 | Anaplastic lymphoma kinase as a new target for the treatment of non-small - cell lung cancer . | ||
1 | The anaplastic lymphoma kinase ( ALK ) gene rearrangement identifies a distinct molecular subset in non-small-cell lung cancer ( NSCLC ) populations susceptible to targeted inhibition . | ||
2 | It consists of a small inversion in the short arm of chromosome 2 between exon 20 of the ALK gene and different exons of the echinoderm microtubule-associated protein -like ( EML4 ) gene . | ||
3 | This translocation leads to a chimeric protein with constitutive activation of ALK that possesses an oncogenic activity demonstrated both in vitro and in vivo . | ||
4 | Other rare translocation partners for ALK other than EML4 may be found in lung cancers , including TRK-fused gene ( TFG ) and kinesin family member 5B ( KIF5B ) . | ||
5 | ALK-positive patients represent 5-6% of all NSCLCs and they seem to have particular clinicopathological and molecular features . | ||
6 | Μ | Recently , Phase I-II trial results of crizotinib , a potent dual c-MET and ALK inhibitor , demonstrated its dramatic efficacy in ALK-positive patients with advanced NSCLC . | |
7 | This article will present knowledge on the characteristics of ALK-positive patients , discuss the different methods of ALK rearrangement detection and focus on clinical results of crizotinib . |
PMID: 21466358 (Patient) Terms: |
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0 | Genetic abnormalities in pancreatic cancer . | ||
1 | CONTEXT : | ||
2 | The neurotrophic tyrosine kinase receptors NTRK1 and NTRK2 have been implicated in the pathogenesis of lung carcinomas . | ||
3 | NTRK receptor expression has been reported in lung carcinomas ; however , the clinical utility of immunohistochemical expression of these receptors is unclear . | ||
4 | OBJECTIVE : | ||
5 | To compare the immunohistochemical expression profiles of NTRK1 and NTRK2 in various histologic subtypes of lung carcinomas and correlate with patient outcome . | ||
6 | DESIGN : | ||
7 | Six hundred eighty-six unique lung cancer cases ( including squamous cell carcinoma , adenocarcinoma , large cell carcinoma , small cell carcinoma , and carcinoid tumor ) with clinical outcome data in tissue microarray format were immunohistochemically stained for NTRK1 and NTRK2 using commercially available antibodies , automated immunostaining , and standard protocols . | ||
8 | RESULTS : | ||
9 | Expression of both NTRK1 and NTRK2 correlates strongly with squamous histology . | ||
10 | NTRK1 and NTRK2 are highly specific markers ( 1 : 92.8% , 2 : 96.4% ) of squamous lung carcinoma when compared with the other carcinoma subtypes , including adenocarcinoma . | ||
11 | Positive NTRK2 staining in squamous carcinoma correlates with improved disease-specific survival ( P <001 ) and overall survival ( P = 047 ) . | ||
12 | CONCLUSIONS : | ||
13 | NTRK1 and NTRK2 are potentially useful immunohistochemical markers that may be particularly helpful in separating squamous cell carcinoma from adenocarcinoma . |
PMID: 21242122 (Cell) Terms: |
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0 | ✓ | Role and relevance of TrkB mutations and expression in non-small cell lung cancer . | GM-MRK-DS, GE-MRK-DS |
1 | PURPOSE : | ||
2 | TrkB has been involved in poor cancer outcome . | ||
3 | TrkB mutations have been reported in non-small cell lung cancer . | ||
4 | In this study , we aimed at characterizing the role of three potentially sensitizing TrkB mutations previously reported in lung cancer . | ||
5 | EXPERIMENTAL DESIGN : | ||
6 | We characterized three activation loop mutants of TrkB ( M713I , R715G , and R734C ) in terms of pathway activation/phosphorylation , migration , anchorage -independent growth , and sensitivity to a Trk inhibitor , using NIH3T3 cells and Baf3 cells . | ||
7 | We also sequenced the tyrosine kinase domain of TrkB in a large number of lung cancer samples of East-Asian origin and cell lines . | ||
8 | RESULTS : | ||
9 | None of the mutants were constitutively active in NIH3T3 transformation and migration assays . | ||
10 | Μ | M713I and R734C mutants showed low levels of autophosphorylation in comparison with wild-type TrkB . | |
11 | Although R715G showed similar level of autophosphorylation to wild-type TrkB on brain-derived neurotrophic factor stimulation , the mutant was not as competent as wild-type TrkB in supporting interleukin-3 -independent growth of Baf3 cells . | ||
12 | In addition , the Trk inhibitor AZD6918 inhibited wild-type TrkB -induced cell migration and cell growth , whereas the mutants were relatively resistant to the Trk inhibitor compared with wild-type TrkB . | ||
13 | We could not confirm the presence of nonsynonymous mutation in 78 lung cancer samples and 29 cell lines . | ||
14 | CONCLUSIONS : | ||
15 | Wild-type , but not mutant , TrkB enhances cell migration and transformation . | ||
16 | Our study suggests that TrkB mutations should not be used for selection of patients with lung cancer treated with Trk inhibitors . | ||
17 | High expression of wild-type TrkB might be beneficial for studies of Trk inhibitors . |
PMID: 21107086 (Patient) Terms: |
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0 | Optimal immunohistochemical markers for distinguishing lung adenocarcinomas from squamous cell carcinomas in small tumor samples . | ||
1 | The histologic subtype of non-small cell lung carcinoma is important in selecting appropriate chemotherapy for patients with advanced disease . | ||
2 | As many of these patients are not operative candidates , they are treated medically after biopsy for diagnosis . | ||
3 | Inherent limitations of small biopsy samples can make distinguishing poorly differentiated lung adenocarcinoma ( ADC ) from squamous cell carcinoma ( SCC ) difficult . | ||
4 | The value of histochemical and immunohistochemical markers to help separate poorly differentiated ADC from SCC in resection specimens is well established ; however , the optimal use of markers in small tissue samples has only recently been examined and the correlation of marker expression in small tissue samples with histologic subtype determined on resection specimens has not been well documented . | ||
5 | We address this issue by examining the expression of 9 markers ( p63 , TTF1 , CK5/6 , CK7 , 34betaE12 , Napsin A , mucicarmine , NTRK1 , and NTRK2 ) on 200 cases of ADC and 225 cases of SCC in tissue microarray format to mimic small tissue specimens . | ||
6 | The single best marker to separate ADC from SCC is p63 ( for SCC : sensitivity 84% , specificity 85% ) . | ||
7 | Logistic regression analysis identifies p63 , TTF1 , CK5/6 , CK7 , Napsin A , and mucicarmine as the optimal panel to separate ADC from SCC . | ||
8 | Reduction of the panel to p63 , TTF1 , CK5/6 , and CK7 is marginally less effective but may be the best compromise when tissue is limited . | ||
9 | We present an algorithm for the stepwise application of p63 , TTF1 , CK5/6 , CK7 , Napsin A , and mucicarmine in situations in which separation of ADC from SCC in small specimens cannot be accomplished by morphology alone . |
PMID: 21080208 (Cell) Terms: in vivo, in vitro, xenograft, mice |
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0 | Evaluation of a multi - kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo . | ||
1 | Kinases have been studied as potential cancer targets because they play important roles in the cellular signaling of tumors . | ||
2 | A number of small molecules targeting kinases are prescribed in clinics and many kinase inhibitors are being evaluated in the clinical phase . | ||
3 | Previously , we discovered a series of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors . | ||
4 | One of the compounds , KRC-108 , has been evaluated as an anti-cancer agent in vitro and in vivo . | ||
5 | A kinase panel assay exhibited that KRC-108 is a potent inhibitor of Ron , Flt3 and TrkA as well as c-Met . | ||
6 | Moreover , KRC-108 inhibited oncogenic c-Met M1250T and Y1230D more strongly than wild type c-Met . | ||
7 | The anti-proliferative activity of KRC-108 was measured by performing a cytotoxicity assay on a panel of cancer cell lines . | ||
8 | The GI ( 50 ) values ( i.e. , 50% inhibition of cell growth ) for KRC-108 ranged from 0.01 to 4.22 muM for these cancer cell lines . | ||
9 | KRC-108 was also effective for the inhibition of tumor growth in human HT29 colorectal cancer and NCI-H441 lung cancer xenograft models in athymic BALB/c nu/nu mice . | ||
10 | This molecule should serve as a useful lead for inhibitors targeting kinases and may lead to new therapeutics for the treatment of cancer . |
PMID: 20524922 (None) Terms: this review |
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0 | Neurotrophins in lung health and disease . | ||
1 | Neurotrophins ( NTs ) are a family of growth factors that are well-known in the nervous system . | ||
2 | Μ | There is increasing recognition that NTs ( nerve growth factor , brain-derived neurotrophic factor and NT3 ) and their receptors ( high-affinity TrkA , TrkB and TrkC , and low-affinity p75NTR ) are expressed in lung components including the nasal and bronchial epithelium , smooth muscle , nerves and immune cells . | |
3 | NT signaling may be important in normal lung development , developmental lung disease , allergy and inflammation ( e.g. , rhinitis , asthma ) , lung fibrosis and even lung cancer . | ||
4 | In this review , we describe the current status of our understanding of NT signaling in the lung , with hopes of using aspects of the NT signaling pathway in the diagnosis and therapy of lung diseases . |
PMID: 18975135 (Patient) Terms: |
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0 | Management of gastrointestinal stromal tumors : from diagnosis to treatment . | ||
1 | Lung tumor cell DNA copy number alteration ( CNA ) was expected to display specific patterns such as a large-scale amplification or deletion of chromosomal arms , as previously published data have reported . | ||
2 | Peripheral blood mononuclear cell ( PBMC ) CNA however , was expected to show normal variations in cancer patients as well as healthy individuals , and has thus been used as normal control DNA samples in various published studies . | ||
3 | We performed array CGH to measure and compare genetic changes in terms of the CNA of PBMC samples as well as DNA isolated from tumor tissue samples , obtained from 24 non-small cell lung cancer patients . | ||
4 | Μ | Contradictory to expectations , our studies showed that the PBMC CNA also showed chromosomal variant regions . | |
5 | The list included well-known tumor-associated NTRK1 , FGF8 , TP53 , and TGFbeta1 genes and potentially novel oncogenes such as THPO ( 3q271 ) , JMJD1B , and EGR1 ( 5q312 ) , which was investigated in this study . | ||
6 | The results of this study highlighted the connection between PBMC and tumor cell genomic DNA in lung cancer patients . | ||
7 | However , the application of these studies to cancer prognosis may pose a challenge due to the large amount of information contained in genetic predisposition and family history that has to be processed for useful downstream clinical applications . |
PMID: 18726896 (Patient) Terms: |
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0 | Expression of TSLC1 , a candidate tumor suppressor gene mapped to chromosome 11q23 , is downregulated in unfavorable neuroblastoma without promoter hypermethylation . | ||
1 | Although it has been well documented that loss of human chromosome 11q is frequently observed in primary neuroblastomas , the smallest region of overlap ( SRO ) has not yet been precisely identified . | ||
2 | Previously , we performed array-comparative genomic hybridization ( array-CGH ) analysis for 236 primary neuroblastomas to search for genomic aberrations with high-resolution . | ||
3 | Μ | In our study , we have identified the SRO of deletion ( 10-Mb or less ) at 11q23 . | |
4 | Within this region , there exists a TSLC1/IGSF4/CADM1 gene ( Tumor suppressor in lung cancer 1/Immunoglobulin superfamily 4/Cell adhesion molecule 1 ) , which has been identified as a putative tumor suppressor gene for lung and some other cancers . | ||
5 | Consistent with previous observations , we have found that 35% of primary neuroblastomas harbor loss of heterozygosity ( LOH ) on TSLC1 locus . | ||
6 | In contrast to other cancers , we could not detect the hypermethylation in its promoter region in primary neuroblastomas as well as neuroblastoma-derived cell lines . | ||
7 | Μ | The clinicopathological analysis demonstrated that TSLC1 expression levels significantly correlate with stage , Shimada's pathological classification , MYCN amplification status , TrkA expression levels and DNA index in primary neuroblastomas . | |
8 | The immunohistochemical analysis showed that TSLC1 is remarkably reduced in unfavorable neuroblastomas . | ||
9 | Furthermore , decreased expression levels of TSLC1 were significantly associated with a poor prognosis in 108 patients with neuroblastoma . | ||
10 | Additionally , TSLC1 reduced cell proliferation in human neuroblastoma SH-SY5Y cells . | ||
11 | Collectively , our present findings suggest that TSLC1 acts as a candidate tumor suppressor gene for neuroblastoma . |
PMID: 18293376 (Patient) Terms: |
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0 | Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung . | ||
1 | The neurotrophic tyrosine receptor kinase ( NTRK ) family is potentially implicated in tumorigenesis and progression of several neoplastic diseases , including lung cancer . | ||
2 | We investigated a large number of pulmonary neuroendocrine tumors ( PNETs ) and non-small cell lung carcinomas ( NSCLCs ) without morphological evidence of neuroendocrine differentiation for mutations in the NTRK gene family . | ||
3 | A total of 538 primary lung carcinomas , including 17 typical carcinoids ( TCs ) , 10 atypical carcinoids ( ACs ) , 39 small cell lung carcinomas ( SCLCs ) , 29 large cell neuroendocrine carcinomas ( LCNECs ) , and 443 NSCLCs were evaluated by single-strand conformation polymorphism ( SSCP ) and sequencing of the tyrosine kinase domain ( TKD ) of NTRK1 , NTRK2 , and NTRK3 . | ||
4 | Μ | The NTRK1 gene was never found to be mutated . | |
5 | Μ | A total of 10 somatic mutations were detected in NTRK2 and NTRK3 , mostly located in the activating and catalytic loops . | |
6 | NTRK mutations were seen in 9 ( 10% ) out of 95 PNETs but in 0 out of 443 NSCLCs investigated . | ||
7 | Μ | No mutations were observed in TCs , ACs , and SCLCs . | |
8 | Interestingly , all the mutations were restricted to the LCNEC histotype , in which they accounted for 31% of cases . | ||
9 | Μ | A mutational analysis , performed after microdissection of LCNECs combined with adenocarcinoma ( ADC ) , showed that only neuroendocrine areas were positive , suggesting that NTRK mutations are involved in the genesis of the neuroendocrine component of combined LCNECs . | |
10 | Our data indicate that somatic mutations in the TKD of NTRK genes are frequent in LCNECs . | ||
11 | Such mutational events could represent an important step in the cancerogenesis of these tumors and may have potential implications for the selection of patients for targeted therapy . |
PMID: 17600921 (None) Terms: |
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0 | [ Expression peculiarities of EGR1 , neurotrophins and their receptor genes in human lung cancer and in normal lung tissue ] . | ||
1 | Expression of certain neurotrophin genes and their receptors , as well as NGF -induced gene EGRI was studied in human normal lung , squamous cell lung cancer , and adenocarcinoma tissues . | ||
2 | Differential expression pattern of NGF , BDNF , and NT-3 mRNA was established by RT-PCR in normal human lung . | ||
3 | Μ | NGF expression level varying from minor to significant was demonstrated in double specimens ( histologically diagnosed human lung cancer and appropriate adjacent tissue ) . | |
4 | Μ | Interestingly , a half of the double specimens studied demonstrated the differential expression pattern in both cancer and adjacent tissues , whereas in other cases no difference in the NGF expression between these pair of tissues was observed . | |
5 | Μ | In the majority of the double specimens , we detected low levels of NT3 and BDNF expression for both cancer and adjacent tissue . | |
6 | Μ | No expression of TrkA , TrkB , p75 was found in double specimens and normal tissues . | |
7 | Μ | Differential expression patterns of TrkC were observed in normal tissues as well as in certain double specimens . | |
8 | Μ | High levels of EGR1 expression were detected in normal tissues . | |
9 | Μ | No EGRI expression was observed in cancer tissue compared to its high expression level in adjacent tissue in the majority of double specimens . |
PMID: 17201587 (Patient) Terms: |
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0 | BRAF mutations in papillary thyroid carcinoma . | ||
1 | Papillary thyroid carcinoma ( PTC ) is the most frequent malignant neoplasm of the thyroid originating from the thyroid follicular cell ( TFC ) . | ||
2 | Although the formation of PTC is believed to result from rearrangements of RET or TRK oncogenes or MET point mutations , these structural aberrations or point mutations do not correlate with the clinicopathological features of PTC and do not seem to be a useful prognostic marker of the disease . | ||
3 | Therefore , further experiments should be carried out in order to find new practical clinical markers . | ||
4 | Recently , oncogene BRAF has become a subject of great interest . | ||
5 | The mutation of BRAF gene is characteristic for PTC and poorly differentiated and/or undifferentiated cancers derived from PTC . | ||
6 | Μ | The occurrence of BRAF mutation has often been observed in various human tumours . | |
7 | The presence of mutation was confirmed in melanoma , colon cancer , gliomas and lung cancer . | ||
8 | In the majority of cases , there is only one type of point mutation - V600E . | ||
9 | The RAS/RAF/MEK/MAPK kinase pathway mediates the cellular response to mitogenic signals . | ||
10 | BRAF gene mutation results in increased kinase activity , leading to excessive activation of the above mitogenic pathway and to uncontrolled proliferation of cancer cells . | ||
11 | Some correlation was noticed between BRAF gene mutation and the clinical stage of the neoplastic disease in question . | ||
12 | Preliminary investigations indicate that the presence of BRAF mutation might be a valuable diagnostic and prognostic marker of the disease . | ||
13 | Further investigations could also bring further improvements into the therapeutic management of thyroid cancer . | ||
14 | There are reports emphasizing the possibility of using the inhibitors of BRAF proteins in the treatment of PTC . | ||
15 | Certainly , in order to confirm the diagnostic usefulness of this marker , further studies should be carried out . |
PMID: 16862449 (None) Terms: |
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0 | The Trk tyrosine kinase inhibitor K252a regulates growth of lung adenocarcinomas . | ||
1 | The neurotrophin family of growth factors and their receptors support the survival of several neuronal and non-neuronal cell populations during embryonic development and adult life . | ||
2 | Neurotrophins are also involved in malignant transformation . | ||
3 | To seek the role of neurotrophin signaling in human lung cancer we studied the expression of neurotrophin receptors in human lung adenocarcinomas and investigated the effect of the neurotrophin receptor inhibitor K252a in A549 cell survival and colony formation ability in soft agar . | ||
4 | We showed that human lung adenocarcinomas express TrkA and TrkB , but not TrkC ; A549 cells , derived from a human lung adenocarcinoma , express mRNA transcripts encoding nerve growth factor ( NGF ) , brain-derived neurotrophic factor ( BDNF ) , TrkA , TrkB , and p75 , and high protein levels of TrkA and TrkB . | ||
5 | Stimulation of cells using NGF or BDNF activates the anti-apoptotic protein Akt . | ||
6 | Interestingly , inhibition of neurotrophin receptor signaling using K252a prevents Akt activation in response to NGF or BDNF , induces apoptotic cell death , and diminishes the ability of A549 cells to growth in soft agar . | ||
7 | The data suggest that neurotrophin signaling inhibition using k252a may be a valid therapy to treat patients with lung adenocarcinomas . |
PMID: 12213675 (Cell) Terms: in vivo, in vitro |
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0 | Nerve growth factor and retinoic acid interactions in the control of small cell lung cancer proliferation . | ||
1 | OBJECTIVE : | ||
2 | Nerve growth factor ( NGF ) has antiproliferative and differentiating effects in neuroendocrine tumors . | ||
3 | In cell lines derived from small cell lung cancer ( SCLC ) , NGF treatment stimulates NGF receptor expression , activates NGF secretion , inhibits proliferation and abrogates invasion . | ||
4 | Since these effects are lost upon NGF withdrawal , it is relevant to identify other differentiation factors that may co-operate with the NGF system to control SCLC growth and differentiation . | ||
5 | DESIGN : | ||
6 | Retinoic acid ( RA ) , which has been shown to inhibit cell transformation and proliferation , modulates the expression of NGF receptors and the sensitivity to NGF in different cell models . | ||
7 | In the present study , we have investigated whether NGF and RA may interact to control the proliferation of SCLC cell lines . | ||
8 | METHODS : | ||
9 | SCLC cells were exposed to 50 ng/ml NGF or 1 microM all-trans RA for different times . | ||
10 | Cell proliferation was measured by the [(3) H]thymidine incorporation test and NGF receptor expression was evaluated by immunofluorescence . | ||
11 | RESULTS : | ||
12 | Μ | We found that RA increased the expression of both trkA and p75 NGF receptors in NCI-N-592 and GLC8 cell lines and prevented the loss of both NGF production and NGF receptor expression occurring when NGF treatment was discontinued . | |
13 | As a result , RA , which did not inhibit the proliferation of untreated cells , abolished NGF withdrawal-related increase in cell proliferation both in vitro and in vivo , thus making permanent the antiproliferative effects of NGF . | ||
14 | CONCLUSIONS : | ||
15 | These data suggest that combined treatments with NGF and RA or mimicking drugs may represent a strategy to be further investigated for the treatment of SCLC . |
PMID: 11956658 (Cell) Terms: |
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0 | Expression of human GIPC1 in normal tissues , cancer cell lines , and primary tumors . | ||
1 | GIPC1/RGS19IP1/GIPC , GIPC2 , and GIPC3 are a family of central PDZ-domain proteins with GH1 and GH2 domains . | ||
2 | GIPC1 interacts with GTPase -activating protein RGS19/RGS-GAIP , TGFbeta type III receptor , receptor tyrosine kinase TrkA , and integrin alpha6A subunit . | ||
3 | Xenopus homologue of human GIPCs interacts with Frizzled-3 class of WNT receptor . | ||
4 | We investigated expression of human GIPC1 mRNA in normal tissues , cancer cell lines , and primary tumors . | ||
5 | GIP1A probe ( nucleotide position 1075-1483 of GIPC1 cDNA ) hybridized to GIPC1 mRNA of 1.8 kb in size . | ||
6 | GIPC1 mRNA was almost ubiquitously expressed in various normal tissues . | ||
7 | Expression level of GIPC1 mRNA was relatively lower in bone marrow and peripheral blood leukocytes . | ||
8 | GIPC1 mRNA was relatively highly expressed in gastric cancer cell lines OKAJIMA , TMK1 , MKN28 , MKN45 , MKN74 , KATO-III , pancreatic cancer cell line AsPC-1 , colorectal cancer cell line SW480 , and lung cancer cell line A549 . | ||
9 | On the other hand , GIPC1 mRNA was almost undetectable in leukemia/lymphoma cell lines HL-60 , Raji , and Daudi . | ||
10 | Expression of GIPC1 mRNA was down-regulated in 12 out of 14 cases of primary kidney tumors , 10 out of 18 cases of primary colorectal tumors , 3 out of 8 cases of primary gastric cancer , 3 out of 3 cases of primary prostate cancer . | ||
11 | Because GIPC1 induces increased expression of TGFbeta type III receptor at the cell surface and enhanced responsiveness to TGFbeta , down-regulation of GIPC1 mRNA in tumors might promote cellular proliferation through interference of TGFbeta signaling . |
PMID: 11694449 (Patient) Terms: , rat |
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0 | Neurotrophins and neurotrophin receptors in human lung cancer . | ||
1 | The expression of neurotrophins ( NTs ) and related high - and low-affinity receptors was studied in surgical samples of histologically diagnosed human tumors of the lower respiratory tract . | ||
2 | The experiment was conducted with 30 non-small cell lung cancer specimens and in eight small cell lung cancer specimens by Western blot analysis and immunohistochemistry to assess expression and distribution of NT and NT receptor proteins in tissues examined . | ||
3 | Immunoblots of homogenates from human tumors displayed binding of anti-nerve growth factor ( NGF ) , brain-derived neurotrophic factor ( BDNF ) , and NT-3 antibodies as well as of anti-tyrosine-specific protein kinase ( Trk ) A , TrkB , and TrkC receptor antibodies , with similar migration characteristics than those displayed by human beta-NGF and proteins from rat brain . | ||
4 | A specific immunoreactivity for NTs and NT receptors was demonstrated in vessel walls , stromal fibroblasts , immune cells , and sometimes within neoplastic cell bodies . | ||
5 | Approximately 33% of bronchioloalveolar carcinomas exhibited a strong membrane NGF and TrkA immunoreactivity , whereas 46% adenocarcinomas expressed an intense TrkA immunoreactivity but a weak immunostaining for NGF within tumor cells . | ||
6 | Moreover , squamous cell carcinomas developed an intense TrkA immunoreactivity only within stroma surrounding neoplastic cells . | ||
7 | A faint BDNF and TrkB immunoreactivity was documented in adenocarcinomas , squamous cell carcinomas , and small cell lung cancers . | ||
8 | NT-3 and its corresponding TrkC receptor were found in a small number of squamous cell carcinomas within large-size tumor cells . | ||
9 | Μ | No expression of low-affinity p75 receptor protein was found in tumor cells . | |
10 | The detection of NTs and NT receptor proteins in tumors of the lower respiratory tract suggests that NTs may be involved in controlling growth and differentiation of human lung cancer and/or influencing tumor behavior . |
PMID: 7538048 (Cell) Terms: |
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0 | Nerve growth factor stimulates clonal growth of human lung cancer cell lines and a human glioblastoma cell line expressing high-affinity nerve growth factor binding sites involving tyrosine kinase signaling . | ||
1 | The growth of a panel of 22 different human tumor , leukemia , and lymphoma cell lines was examined in a human tumor cloning assay in agar or methylcellulose and a tritiated thymidine uptake assay . | ||
2 | The cultures were performed in the absence or presence of increasing concentrations ( 05-500 ng/ml ) of nerve growth factor ( NGF ) . | ||
3 | The growth of 17 of the 22 cell lines was not significantly and reproducibly affected by NGF . | ||
4 | There was minor ( 12-fold ) but reproducible stimulation of clonal growth in one glioblastoma cell line ( 86-HG-39 ) by NGF , but in this cell line NGF induced no growth modulation in a tritiated thymidine uptake assay . | ||
5 | However , clonal growth of another glioblastoma cell line ( 87-HG-31 ) and all three lung cancer cell lines tested ( HTB 119 , HTB 120 , CCL 185 ) could be stimulated up to 3-fold by NGF with a dose-response relationship for the growth factor . | ||
6 | Growth stimulation by NGF could be completely reversed by neutralizing anti-NGF antibody and by the tyrosine kinase inhibitor genistein . | ||
7 | Evaluation of secondary plating efficiency revealed the stimulation of colony formation as representing self-renewal and not terminal differentiation . | ||
8 | ✓ Μ | Reverse transcriptase-PCR experiments in the five responding cell lines showed expression of both low-affinity NGF receptor (glycoprotein 75) and c-trk transcripts on the mRNA level . | RO-ASS-GE |
9 | Μ | Of the five responding cell lines , only 86-HG-39 , the cell line with the lowest responsiveness , revealed low-affinity NGF receptor on the protein level ; the other four cell lines with high responsiveness , including the three lung cancer cell lines , expressed no low-affinity NGF receptor as shown by fluorescence-activated cell sorter analysis and immunoprecipitation using the ME 20.4 antibody . | |
10 | Immunoprecipitation using anti-trk antibodies was negative in all five responding cell lines . | ||
11 | Μ | However , binding studies with iodinated NGF showed only low-affinity binding on the 86-HG-39 cell line and only high-affinity binding on the high-responder cell lines CCL 185 and 87-HG-31 . | |
12 | In summary , our data suggest that NGF can be operative in stimulation of clonal growth of malignant tumor cells . | ||
13 | High-affinity but not low-affinity binding sites mediate signal transduction for clonal growth and signaling involves tyrosine kinase activity . |
PMID: ASCO_135058-144 (Patient) Terms: |
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0 | Analysis of NTRK1 gene fusion incidence in an unselected cohort of non-small cell lung cancer patients. . | ||
1 | Background : The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions . | ||
2 | We recently discovered a new oncogenic fusion involving NTRK1 that can be targeted by kinase inhibitors against the TRK family of receptor tyrosine kinases . | ||
3 | We therefore investigated NTRK1cytogenetic patterns of tumor samples from NSCLC patients to determine the incidence and clinical characteristics of patients in this unselected cohort . | ||
4 | Methods : A tumor microarray ( TMA ) previously analyzed by ALK ( 12/445 = 27% ) , ROS1 ( 5/429 = 12% ) and RET ( 6/348 = 17% ) FISH containing 447 tumor samples from patients with NSCLC was analyzed . | ||
5 | Clinical characteristics of the TMA have been reported previously . | ||
6 | Fluorescence in situ hybridization ( FISH ) screening using a novel dual color NTRK1 break-apart assay was performed . | ||
7 | RT-PCR was performed on RNA extracted from corresponding tumor blocks to confirm the presence and identify of the NTRK1fusion partner . | ||
8 | A novel proximity-ligation assay ( PLA ) to detect TRKA activation by detecting TRK-SHC1 protein complexes was developed as a complimentary , proteomic method for the detection of TRK activation , regardless of the mechanism of activation . | ||
9 | Results : NTRK1 FISH analysis was successfully performed on 443 of 447 tumor samples ( 991% ) . | ||
10 | Five of 443 ( 11% ) tumor samples exhibited patterns indicating an NTRK1 rearrangement with split ( n = 1 ) , single 3 ( n = 1 ) , or single 5 ( n = 3 ) signals . | ||
11 | Clinical characteristics of the 5 NTRK1+ patients are as follows : 3 female ; 2 never-smokers ; and 3 adenocarcinoma , 1 squamous cell carcinoma , and 1 large cell neuroendocrine carcinoma histology . | ||
12 | Μ | An additional 5 samples had atypical cytogenetic patterns and 7 samples demonstrated focal NTRK1gene amplification warranting further exploration by alternate methodologies . | |
13 | Conclusions : NTRK1 gene rearrangements were detected in 1.1% of tumor samples from an unselected cohort of NSCLC patients . | ||
14 | Additional NTRK1 cytogenetic patterns were observed and warrant further evaluation . | ||
15 | Confirmatory testing by PCR to evaluate the specific NTRK1 fusion transcripts and a novel TRK PLA method will be presented . |
PMID: AACR_2014-4656 (Patient) Terms: |
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0 | The novel mRNA in situ hybridization method for the detection of ALK , RET , ROS1 and NTRK1 mRNA in non-small cell lung cancer . | ||
1 | [Background]In recent years , tumor genotyping is critical for making decisions of non-small cell lung cancer ( NSCLC ) treatment . | ||
2 | However genetic rearrangement of ALK , RET , ROS1 and NTRK1 were identified in the subset of NSCLC patients , these clinical characteristics were still remained to be clear . | ||
3 | Immunohistochemistry ( IHC ) is widely used as a simple and quick method for screening for protein expression of these oncogenes . | ||
4 | Fluorescence in situ hybridization ( FISH ) or RT-PCR are performed consecutively to confirm the genotyping . | ||
5 | However it is often taking time and expensive and it is needed to consolidate novel substitute methods.[Purpose]We performed the in situ hybridization ( ISH ) analysis to detect cellular mRNA in formalin-fixed paraffin-embedded ( FFPE ) tissue samples of lung cancer . | ||
6 | Μ | We also conducted IHC with the use of ALK , RET , ROS1 and NTRK1 specific antibodies and investigate a comparative study to assess the usefulness of mRNA-ISH to detect expression of these mRNA.[Materials and Methods]We made tissue micro array ( TMA ) slides using 40 FFPE samples of resected lung adenocarcinoma with known epidermal growth factor receptor ( EGFR ) mutation status by PCR ( PNA-LNA PCR clamp method ) . | |
7 | The mRNA in situ hybridization was employed using RNA scope R 2.0 Regant Kit with targeting probes . | ||
8 | IHC staining was conducted by antibodies using 5A4 and D5F3 for ALK , RET01 for RET , D4D6 for ROS1 , and 14G6 for NTRK1.[Results]All of the IHC stained cases were clearly detected by mRNA-ISH respectively . | ||
9 | There were some cases which were only visualized by ISH , each case was partially positive and not totally of the tumor . | ||
10 | ALK : | ||
11 | 5% of cases ( 2 out of 40 ) were detected in mRNA-ISH and were strongly stained with both 5A4 and D5F3 . | ||
12 | RET : | ||
13 | 20% of cases ( 8/40 ) were detected in mRNA-ISH . | ||
14 | Two cases ( 5% of total ) had positive RET01 staining , while 6 cases had negative staining. ( 3 had no other genetic alterations , 2 had EGFR-L858R confirmed by PCR , and 1 had ALK by IHC and FISH ) ROS1 : 20% ( 8/40 ) were detected in mRNA-ISH . | ||
15 | Μ | Three cases ( 75% of total ) presented positive D4D6 staining , while 5 had negative staining. ( 3 had no other alterations , 1 had EGFR-E746-A750 and 1 had EGFR-L858R by PCR ) NTRK1 : 17.5% of cases ( 7/40 ) were detected in mRNA-ISH. 1 case ( 25% of total ) presented positive 14G6 staining , while 6 cases had negative staining. ( 2 had no other alterations , 2 had EGFR-L858R , 1 had EGFR-E746-A750 , and 1 had ALK ) [Conclusion] The novel mRNA in situ hybridization method combined with traditional IHC could improve detection rate of ALK , RET , ROS1 and NTRK1 gene alterations in NSCLC FFPE samples . |
PMID: ASCO_147329-156 (Patient) Terms: retrospective |
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0 | Clinical implementation of anchored multiplex PCR with targeted next-generation sequencing for detection of ALK , ROS1 , RET and NTRK1 fusions in non-small cell lung carcinoma. . | ||
1 | Background : Chromosomal rearrangements resulting in expression of oncogenic receptor tyrosine kinase fusions occur in a subset of epithelial malignancies and can underlie sensitivity to tyrosine kinase inhibitors . | ||
2 | In non-small cell lung cancer ( NSCLC ) , rearrangements involving anaplastic lymphoid kinase ( ALK ) , ROS proto-oncogene 1 ( ROS1 ) , and RET proto-oncogene ( RET ) occur at frequencies of approximately 4% , 1% and 1% , respectively . | ||
3 | Rearrangements involving neurotrophic tyrosine kinase receptor type 1 ( NTRK1 ) have been described , though the frequency is not well characterized . | ||
4 | Methods : We implemented a multiplex polymerase chain reaction ( PCR ) technology , Anchored Multiplex PCR ( AMP ) , for detection of fusion transcripts using targeted next-generation sequencing of cDNA generated from clinical samples ( Zheng et al , 2014 ) . | ||
5 | The sequencing library targets known fusion exons in ALK , ROS1 , RET and NTRK1 . | ||
6 | We retrospectively reviewed the NSCLC cases assessed by this method . | ||
7 | Μ | Results : Between July 2013 and January 2015 , 663 clinical NSCLC cases from our institution were assessed , providing > 99% power to detect atleast one fusion event at an underlying frequency as low as 1%. 584 cases were adenocarcinoma histology . | |
8 | We detected fusions involving ALK , ROS1 , RET and NTRK1 at frequencies of 2.6% , 0.9% , 2.0% and 0.0% ( 17 , 6 , 13 and 0 cases ) , respectively . | ||
9 | All were mutually exclusive . | ||
10 | The histologic subtype was adenocarcinoma in all fusion cases except one . | ||
11 | The average age at diagnosis was 57.0 , 55.9 and 58.3 years , and average pack years were 8.5 , 5.8 and 7.7 for patients with ALK , ROS1 and RET fusions , respectively . | ||
12 | The ALK fusion partner in all cases was EML4 ; ROS1 fusion partners were SDC4 , CD74 , and EZR ; and RET fusion partners were KIF5B , CCDC6 , RUFY2 and TRIM24 . | ||
13 | Μ | Although no NTRK1 fusion was detected in NSCLC , we detected a PPL-NTRK1 fusion in a thyroid carcinoma . | |
14 | Conclusions : With this method , we identified ALK , ROS1 and RET fusions at frequencies and with patient characteristics consistent with previous studies . | ||
15 | NTRK1 fusions appear to be rare in NSCLC , though it is possible that this assay may not detect all fusions . |
PMID: AACR_2014-5255 (Cell) Terms: PDX, xenograft, in vitro |
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0 | EGFR is a conspiring kinase in gene fusion positive lung cancer . | ||
1 | The use of kinase inhibitors directed at dominant oncogenes has proven a successful treatment strategy for non-small cell lung cancer ( NSCLC ) harboring ALK gene fusions , but intrinsic or acquired drug resistance limits clinical benefit . | ||
2 | We recently identified a novel class of oncogenes generated by translocations of the NTRK1 gene , which encodes the TRKA receptor tyrosine kinase . | ||
3 | ROS1 and RET gene fusions represent additional oncogene targets in lung cancer and gene fusion positive tumors currently comprise 10% of lung adenocarcinomas . | ||
4 | Previous results from our laboratory have demonstrated that EGFR signaling can mediate both intrinsic and acquired resistance in a ROS1+ NSCLC cell line . | ||
5 | We asked whether EGFR might play a common role in other NSCLC cell lines harboring gene fusions with the aim of developing combination therapies that may delay drug resistance to oncogene -targeted kinase inhibitors in these tumors . | ||
6 | Μ | We have observed high protein expression of the epidermal growth factor receptor ( EGFR ) in NSCLC cell lines positive for ALK ( H3122 , H2228 , and STE-1 ) , ROS1 ( HCC78 and CUTO-2 ) , RET (LC-2/Ad) , and NTRK1 gene fusions (CUTO-3) , and in a NTRK1 patient-derived xenograft ( PDX ) model . | |
7 | We observed increased inhibition of downstream signaling and in vitro cellular proliferation with the addition of EGFR tyrosine kinase inhibitors in these gene fusion positive cell lines . | ||
8 | Furthermore , stimulation of EGFR with EGF rescues targeted inhibition with oncogene -specific kinase inhibitors in the critical downstream signaling pathways such as PI3K/AKT and MEK/ERK . | ||
9 | Inhibition of cellular proliferation of these cell lines using oncogene -specific kinase inhibitors was also rescued by stimulation of EGFR . | ||
10 | Interestingly , we observed transactivation of the TRKA and RET kinase domains by EGFR stimulation in the CUTO-3 and LC-2/Ad cell lines , respectively , despite treatment with a TRKA or RET kinase inhibitor . | ||
11 | Additionally , co-immunoprecipitation experiments show that EGFR and the chimeric protein RIP-TRKA ( encoded by the fusion gene MPRIP-NTRK1 ) associate in the CUTO-3 cells or when ectopically expressed in 293T cells . | ||
12 | Collectively , these data demonstrate a critical role for EGFR in gene fusion positive lung cancer and suggest that signaling via this receptor may provide a survival mechanism for cancer cells treated with an oncogene -specific kinase inhibitor . | ||
13 | Further investigation of EGFR inhibition in addition to oncogene -specific kinase inhibitors may be warranted . |
PMID: AACR_2015-3644 (Cell) Terms: phase I/II, clinical trial, phase III |
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0 | Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer . | ||
1 | All patients with oncogenic driver mutations in non-small cell lung cancer ( NSCLC ) who are treated with a targeted agent will eventually develop resistance . | ||
2 | In an effort to identify inhibitors of NTRK1 and ROS1 , which are inappropriately activated in NSCLC , we created and screened a library of existing targeted drugs against BaF3 cells transformed with these oncogenes . | ||
3 | This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 ( IC50 = 9 nM ) , including the crizotinib-resistant mutants G2032R ( IC50 = 26 nM ) and L2026M ( IC50 = 11 nM ) , with no inhibition of the parental BaF3 cells ( IC50 > 10 M ) . | ||
4 | AP26113 , a dual ALK/EGFR inhibitor undergoing phase I/II clinical trials , also potently inhibited CD74-ROS1 ( IC50 = 4 nM ) , including the crizotinib-resistant mutants G2032R ( IC50 = 206 nM ) and L2026M ( IC50 = 84 nM ) , with weak inhibition of the parental BaF3 cells ( IC50 > 1 M ) . | ||
5 | Both cabozantinib and AP26113 inhibited ROS1 autophosphorylation and downstream ERK activation in CD74-ROS transformed BaF3 cells and in the ROS1-rearranged NSCLC cell line HCC78 . | ||
6 | The FGFR3 inhibitor dovitinib , which is in phase III clinical trials for renal cell carcinoma , potently inhibited NTRK1 compared to parental BaF3 cells ( IC50 = 69 nM versus > 1 M ) , and blocked NTRK1 autophosphorylation and ERK activation . | ||
7 | While acquired resistance to targeted therapies is a major clinical problem , this study highlights other existing agents that may overcome resistance , and identifies several promising candidates for clinical trials . |
PMID: AACR_2015-4891 (Patient) Terms: retrospective |
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0 | Comprehensive genetic profiling of chromosomal translocations in lung cancer tumors : development and validation of a next-generation sequencing panel in an international multicenter study . | ||
1 | Approximately 7% of non-small cell lung carcinomas ( NSCLCs ) harbor oncogenic fusions involving ALK , ROS1 , and RET . | ||
2 | While tumors harboring ALK fusions are highly sensitive to crizotinib , emerging data have demonstrated that individuals with ROS1 or RET fusions may also benefit from inhibitors targeting these two kinases . | ||
3 | A new oncogenic fusion involving NTRK1 that can be targeted by kinase inhibitors has been recently described . | ||
4 | The two main methods to identify translocations , fluorescent in situ hybridization ( FISH ) and Immunohistochemistry ( IHC ) are labor intensive and sensitivity is rather low . | ||
5 | Common sample types for lung cancer analysis are biopsies making the study of more than one fusion gene rather difficult . | ||
6 | In this study we aimed to develop and validate a workflow based on AmpliSeq technology to comprehensively profile ALK , ROS1 , RET and NTRK1 chromosomal translocations in lung tumors . | ||
7 | Two hundred lung cancer retrospective samples , including tumor biopsy , were collected from 12 laboratories - the OncoNetwork Consortium . | ||
8 | All the samples were previously characterized by orthologous techniques ( FISH , IHC , RT-PCR and/or MassArray ) . | ||
9 | More than 30 ALK positive samples were selected . | ||
10 | The panel targets over 70 fusion transcripts associated with ALK , RET , ROS1 , and NTRK1 genes . | ||
11 | The panel also includes 5 and 3 gene expression assays for each gene as indicators of a translocation event and assays for 5 internal control genes . | ||
12 | The workflow is compatible with formalin fixed paraffin embedded ( FFPE ) tissue , requiring only 10ng of total RNA and able to multiplex up to 16 libraries on a single Ion 318 chip.A dedicated data analysis pipeline using the Ion Reporter software 4.2 was evaluated . | ||
13 | Serial dilutions of cell lines RNA harboring known fusion events , in normal RNA showed that the methodology had 1% mutant RNA limit of detection . | ||
14 | A second dilution experiment using RNA extracted from FFPE lung fusion positive samples diluted in a negative FFPE sample showed a detection limit of 15% . | ||
15 | The use of a common control fusion positive RNA samples among all the consortia laboratories showed 100% reproducibility . | ||
16 | Concordance study was performed using 200 FFPE samples previously characterized with standard method . | ||
17 | A concordance of >98% was obtained between the methodologies . | ||
18 | The discordant results are currently under study . | ||
19 | A negative FFPE samples was run as single test on an Ion 318 chip on to evaluate the possibility of false positive results due to high number of reads . | ||
20 | Μ | No false positive was detected in this experiment . | |
21 | In this study we present a workflow that provides a robust , reproducible and accurate comprehensive genetic screening tool well suited for FFPE lung tumor biopsies , in a fast and cost-efficient manner . | ||
22 | This may provide a valuable tool for reducing turn-around-time and expense in lung cancer analysis . |
PMID: ASCO_185816-199 (Patient) Terms: |
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0 | Clinicopathologic features of non-small cell lung cancer ( NSCLC ) harboring an NTRK gene fusion. . | ||
1 | Background : Gene fusions involving NTRK1/2/3 can generate oncoproteins containing the kinase domains of TRKA/B/C , respectively . | ||
2 | Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions . | ||
3 | An estimated 0.1 1% of NSCLCs harbor NTRK fusions . | ||
4 | To date , clinical and radiographic responses to TRK inhibitors have been reported for 2 NTRK fusion-positive NSCLCs ( Farago et al , 2015 ; Hong et al , 2016 ) . | ||
5 | Despite the potential benefit of identifying these fusions , the clinicopathologic features of NTRK fusion NSCLCs are not well characterized . | ||
6 | Methods : Physicians across multiple institutions contributed deidentified cases to an NTRK fusion NSCLC database . | ||
7 | A central pathologist ( MM ) reviewed tumor histology in cases with available tissue . | ||
8 | Results : 10 NSCLC cases with NTRK gene fusions were identified . | ||
9 | Of these , TRK kinase domain -containing potentially activating fusions were verified by next-generation sequencing ( NGS ) in 7 , forming the study cohort . | ||
10 | Fusions involved NTRK1 (6) and NTRK3 (1) with 6 different partners . | ||
11 | Four ( 57% ) patients were male . | ||
12 | Median age at diagnosis was 47.6 years ( range 279 860 ) . | ||
13 | The average smoking pack year history was 8.9 ( range 0 to 30 ) . | ||
14 | Five ( 71% ) presented with metastatic disease . | ||
15 | Μ | No concurrent alterations in KRAS , EGFR , ALK , ROS1 , or other known drivers were identified in the study cohort cases . | |
16 | On pathologic review of 4 cases , all were adenocarcinoma , including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features . | ||
17 | Of the 3 remaining non-study cohort cases , 1 was a non - kinase domain -containing NTRK1 fusion with a concurrent KRAS G12C mutation , 1 was an NTRK2 intragenic deletion disrupting the exon 18 3 splice site , and 1 was an NTRK1 alteration detected by FISH but not verified by NGS and with a concurrent HER2 L755P mutation . | ||
18 | Conclusions : NTRK fusions occur in both men and women across wide ranges in age and smoking history . | ||
19 | Μ | We therefore suggest that all NSCLC adenocarcinomas without other oncogenic driver alterations be screened for NTRK fusions . | |
20 | Notably , not all NTRK alterations are activating , requiring validation of the specific position of the fusion . |
PMID: ASCO_152938-156 (Patient) Terms: |
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0 | A non-invasive liquid biopsy approach for therapeutic stratification of lung cancer patients. . | ||
1 | Background : Liquid biopsies of circulating tumor DNA ( ctDNA ) may eliminate the need for invasive tissue biopsies and allow the detection of alterations in multiple metastatic lesions throughout the course of therapy . | ||
2 | This is of particular importance in lung cancer , where a third of patients may have insufficient biopsies for molecular analyses and may be ineligible for approved targeted therapies . | ||
3 | However , the fraction of ctDNA obtained from a blood sample is often low ( < 10% ) and can be difficult to detect with current approaches . | ||
4 | Μ | Additionally , most methods to detect ctDNA interrogate single hot spot mutations or a few genetic alterations . | |
5 | Μ | Methods : To overcome these issues , we developed comprehensive ctDNA approaches to detect somatic sequence mutations , translocations , and amplifications at low allele frequencies in the circulation of cancer patients . | |
6 | These analyses span 63 well-established cancer genes , including BRAF , EGFR , ERBB2 , PI3KCA , FGFR , KRAS and NRAS , translocations in ALK , EGFR , NTRK1 , RET and ROS1 , and amplification of MET and ERBB2 . | ||
7 | This comprehensive panel covers many recognized resistance mechanisms to targeted therapies and provides a method to understand patterns of intrinsic and acquired resistance in oncogene defined lung cancer . | ||
8 | To evaluate this approach , we performed dilution series using tumor-derived DNA , containing well-characterized somatic mutations , in the presence of wild-type DNA in 3-5ml of plasma from 90 patients with late-stage lung cancer . | ||
9 | Μ | Results : We were able to detect sequence alterations at levels of > 0.01% with a specificity of > 99.9% . | |
10 | Μ | Further analyses demonstrated high concordance between the somatic sequence mutations and translocations identified in the tumor sample and those identified in the plasma , including alterations in driver genes as well as those related to acquired resistance to targeted therapies. 70 patients had serial samples , and within this cohort , we demonstrated evolution of resistance clones that predict radiographic increases in tumor burden . | |
11 | Conclusions : These analyses provide a non-invasive platform to enable liquid biopsy detection of clinically relevant genetic alterations across a large number of genomic loci in lung cancer patients . |
PMID: ASCO_149700-156 (Patient) Terms: clinical trial |
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0 | A comprehensive noninvasive approach for the stratification of lung cancer patients for targeted therapies. . | ||
1 | Background : Cancer is a disease caused by the accumulation of genetic alterations which initiate and promote the uncontrolled growth and metastasis of cancer cells . | ||
2 | These genetic alterations are the targets of multiple approved therapies , preferentially inhibiting cancer cells while limiting damage to normal cells . | ||
3 | Given the advances in the efficacy of targeted therapies , current guidelines recommend molecular testing of specific genes to match patients with targeted therapies for which there is clinical benefit . | ||
4 | However , approximately one-third of non-small cell lung cancer ( NSCLC ) patients lack tissue samples for analysis and are not eligible for targeted therapies . | ||
5 | Circulating tumor DNA ( ctDNA ) , shed into the blood from tumor tissue , contain alterations specific to the genetic profile of the malignancy in tissue and can stratify patients for targeted therapies through a liquid biopsy . | ||
6 | Methods : We have developed LungSelect , a ctDNA approach to interrogate clinically actionable genetic alterations in NSCLC that are recommended by clinical guidelines or targeted in late stage clinical trials . | ||
7 | LungSelect uses digital next-generation sequencing approaches to comprehensively examine single-base mutations , insertions and deletions in BRAF , EGFR , ERBB2 , KRAS and NRAS while assessing translocations in ALK , EGFR , NTRK1 , RET and ROS1with a high degree of precision and accuracy . | ||
8 | Results : To evaluate the analytical sensitivity of LungSelect , we examined well characterized somatic mutations through a combination of tumor derived DNA and wild-type derived DNA at various levels of tumor contribution , achieving a lower limit of detection of > 0.01% with a specificity of > 99.9% . | ||
9 | Μ | In addition , we examined the utility of LungSelect to detect these genetic alterations in late-stage lung cancer patients through comparison of plasma and matched tissue biopsy specimens . | |
10 | Μ | These analyses revealed a high concordance between the genetic alterations identified in plasma and matched tissue biopsies . | |
11 | Μ | Conclusions : LungSelect comprehensively detects genetic alterations non-invasively , allowing for a greater proportion of patients to obtain the survival benefit associated with targeted therapies in NSCLC . |
PMID: ASCO_152919-156 (None) Terms: phase I, NCT02122913, Phase I, tumor inhibition in preclinical models |
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0 | Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode . | ||
1 | Background : TheTRK family of neurotrophin receptors , TRKA , TRKB , and TRKC ( encoded by NTRK1 , NTRK2 , and NTRK3 genes , respectively ) and their neurotrophin ligands regulate growth , differentiation and survival of neurons . | ||
2 | Translocations involving the NTRK1/2/3 kinase domain , mutations involving the TRK ligand -binding site , amplifications of NTRK , TRK splice variants , and autocrine/paracrine signaling have been described in a diverse number of tumor types and may contribute to tumorigenesis . | ||
3 | Recently NTRK1 fusions were described in a subset of adenocarcinoma lung cancer patients ( Vaishnavi , 2013 ) and NTRK2 and NTRK3 fusions have been described in multiple tumor types ( Skalova , 2014 ; Ricarte-Filho , 2013 ; Vaishnavi , 2014 ) . | ||
4 | LOXO-101 is a potent , oral , ATP-competitive pan-TRK inhibitor with IC50 values in the low nanomolar range for inhibition of TRK family members in binding and cellular assays , with 100x selectivity over other kinases . | ||
5 | LOXO-101 has demonstrated tumor inhibition in preclinical models . | ||
6 | Methods : This study ( NCT02122913 ) is an ongoing phase Ia/Ib dose escalation plus expansion trial in adults with advanced solid tumors . | ||
7 | The phase Ia component is an open-label , multicenter , dose escalation trial . | ||
8 | Patients with solid tumors refractory to standard therapy , with normal hematopoietic and major or gan function are eligible for study . | ||
9 | LOXO-101 is administered orally QD or BID for continuous 28-day cycles . | ||
10 | This component of the trial will determine the MTD for LOXO-101 . | ||
11 | The phase Ib component is an open-label , multicenter , global , dose expansion study . | ||
12 | Μ | In addition to the Phase Ia eligibility criteria , patients must have a demonstrated alteration in one of the three NTRK genes or three TRK proteins . | |
13 | The number of expansion cohorts will be determined by the molecular characteristics of the tumors in the patients enrolled . | ||
14 | Data will provide initial evidence of tumor activity of LOXO-101 , stratified by the type of NTRK or TRK alteration or tumor type , as well as further elucidation of the safety profile of LOXO-101 in cancer patients . | ||
15 | Archival tissue is required for further characterization of molecular abnormalities . |
PMID: ASCO_186766-199 (Patient) Terms: |
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0 | Genomic profiling of circulating tumor DNA in small cell lung cancer : comparison of relapsed disease to initial tumor biopsies. . | ||
1 | Background : Genomic studies in small cell lung cancer ( SCLC ) are hampered by the small amounts of biopsy tissue typically available . | ||
2 | Μ | The emergence of liquid biopsy to identify tumor DNA mutations in plasma ( circulating tumor DNA or ctDNA ) has the potential to overcome this restriction and also facilitates multiple sampling during disease treatment . | |
3 | Here we use ctDNA to compare mutation profiles in SCLC and non-small cell lung cancer ( NSCLC ) patients and to identify changes that occur post-relapse in SCLC . | ||
4 | Methods : Targeted exome sequencing of 73 genes in plasma from 13 SCLC and 17 NSCLC patients was obtained along with matched patient targeted exome sequencingof 315 genes for 6 SCLC and 8 NSCLC tumor biopsies . | ||
5 | Only the 70 genes analyzed by both assays were studied . | ||
6 | Results : 3 SCLC and 8 NSCLC ctDNA specimens were collected pre-treatment , with the remainder post-relapse . | ||
7 | Μ | In SCLC , 46 total gene mutations were detected in ctDNA with a mean allelic fraction ( mAF ) of 16.0% . | |
8 | Μ | TP53 ( mAF 308% , N= 15 ) and ARID1A ( mAF 160% , N= 6 ) were the most frequently mutated SCLC genes . | |
9 | Μ | In NSCLC , 53 gene mutations were detected with a mAF of 2.5% . | |
10 | Μ | TP53 ( mAF 59% , N= 13 ) , EGFR ( mAF 23% , N= 10 ) and KRAS ( mAF 44% , N= 5 ) were frequently mutated NSCLC genes. 44 and 10 gene amplifications were detected in SCLC and NSCLC ctDNA , respectively. 5 SCLC patients with tumor DNA profiles obtained pre-treatment had matching ctDNA profiles obtained post-relapse . | |
11 | TP53 mutation status agreed in 4 of the matched specimens. 6 new gene mutations occurred post-relapse in ctDNA , notably a TSC1 mutation ( AF 84% ) in one patient. 7 tumor gene mutations were lost post-relapse , notably ARID1A and NTRK1 mutations were lost in two patients each . | ||
12 | Μ | Remarkably , 23 new gene amplifications were detected post-relapse in ctDNA , including PIK3CA ( N= 5 ) and CCNE1 ( N= 5 ) , whereas only 1 was detected in pre-treatment tumors . | |
13 | Conclusions : SCLC exhibits much greater ctDNA mAF values than NSCLC , although their overall mutation profiles agree with published tumor DNA mutation profiles . | ||
14 | Interestingly , the predominant change observed in SCLC ctDNA profiles in relapsed specimens is increased gene amplification . |
PMID: AACR_2014-4268 (Patient) Terms: |
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0 | An unbiased survey of cancer-related rearrangements in 5,917 solid tumors identifies therapeutically actionable fusions across multiple disease subtypes . | ||
1 | The growing trend to make cancer treatment more precise depends on the accurate identification of clinically actionable genomic alterations within a patient's tumor . | ||
2 | Fusion proteins that result from genomic rearrangements are attractive therapeutic targets because they are tumor-specific and cancer cells depend on their expression for survival . | ||
3 | The goal of this study was to investigate the breadth of genomic rearrangements in 19 genes shown to be fused in atleast one solid cancer across a collection of 5,917 tumors from a diverse variety of subtypes . | ||
4 | All tumor samples were submitted to a CLIA-certified CAP-accredited laboratory ( Foundation Medicine , Cambridge MA ) for next-generation sequencing-based genomic profiling of 3,769 exons from 236 cancer related genes and 47 introns of 19 genes frequently rearranged in cancer . | ||
5 | We observed 350 genomic rearrangements in 338 samples from 82 different solid tumor pathologies . | ||
6 | Rearrangements involving kinases were observed in 176 samples ( 3% of total samples ) . | ||
7 | We identified potentially druggable rearrangements of BRAF ( n = 13 unique partners ; 9 pathologies ) , ALK ( n = 11 unique partners ; 11 pathologies ) , FGFR2 ( n = 9 unique partners ; 6 pathologies ) , ROS1 ( n = 7 unique partners ; 3 pathologies ) , RET ( n = 7 unique partners ; 5 pathologies ) , FGFR3 ( n = 5 unique partners ; 6 pathologies ) , NTRK1 ( n = 3 unique partners ; 3 pathologies ) , ERBB2 ( n = 2 unique partners ; 2 pathologies ) , and ERBB3 ( n = 2 unique partners ; 2 pathologies ) . | ||
8 | ALK , ROS1 , RET , and NTRK1 fusions in lung cancer have all shown sensitivity to targeted agents in patients . | ||
9 | The largest number of genomic rearrangements ( n = 87 ) was found in lung adenocarcinoma ( 12% of cases ) . | ||
10 | Μ | Interestingly , we identified a KIAA1549-BRAF fusion in a triple negative breast cancer sample , a FIP1L1-PDGFRA fusion in glioblastoma , a KIF5B-RET fusion in ovarian cancer , and an NCOA4-RET fusion in colon adenocarcinoma . | |
11 | These fusions have been identified previously in pilocytic astrocytoma , myeloid malignancies , lung cancer and thyroid cancer , respectively , but have rarely been reported outside of these diseases ; importantly , hypereosinophilic syndromes harboring FIP1L1-PDGFRA are sensitive to imatinib , and lung cancers with KIF5B-RET are sensitive to cabozantinib . | ||
12 | Collectively , these data demonstrate that gene fusions exist across a multitude of tumor types and that known fusions are not always confined to the disease in which they appear most often . | ||
13 | These rearrangements include clinically actionable fusions which may identify tumors that are sensitive to selective FDA-approved targeted agents . |
PMID: AACR_2014-1531 (Patient) Terms: |
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0 | Cross-entity mutation analysis of lung neuroendocrine tumors sheds light into their molecular origin and identifies new therapeutic targets . | ||
1 | Lung neuroendocrine tumors ( LNETs ) comprise small-cell lung cancer ( SCLC ) , large-cell neuroendocrine tumors ( LCNEC ) , and pulmonary carcinoids ( PCA ) , and account for 25% of all lung cancer cases . | ||
2 | The low 5-year survival rate of the highly aggressive LNETs ( SCLC and LCNEC ) combined with the lack of an effective treatment , suggest that understanding how these tumors arise and identifying therapeutic targets are unmet needs . | ||
3 | Μ | We performed genome/exome , and transcriptome sequencing of 29 SCLC ( Ref1 ) , 60 LCNEC , and 45 PCA to better understand their molecular origin and identify altered genes that may offer therapeutic opportunities . | |
4 | Μ | In contrast to SCLC and LCNEC , we found that RB1 and TP53 mutations were rare events in PCA suggesting that PCA are not early progenitor lesions of SCLC or LCNEC , but arise through independent mechanisms . | |
5 | Moreover , GSEA analysis showed that genes of the RB1 pathway were downregulated in SCLC but not in PCA . | ||
6 | Our data also show that inactivation of chromatin-remodeling genes , specifically genes involved in histone methylation and subunits of the SWI/SNF complex , is sufficient to drive transformation in PCA . | ||
7 | Μ | In a preliminary analysis of 15 LCNEC ( Ref2 ) we observed a predominance of mutations typical of SCLC , such as RB1 , TP53 , and CREBBP/EP300 . | |
8 | Μ | In this larger series , we additionally found samples with mutations frequent in adenocarcinoma ( AD ) or squamous (SQ) lung cancer . | |
9 | Μ | We could then distinguish two well-defined groups of LCNEC : a SCLC-like group , carrying MYCL1 amplifications and mutations in both RB1 and TP53 genes ; and an AD/SQ-like group , harbouring CDKN2A deletions , TTF1 amplifications , and frequent mutations in KEAP1 and STK11 . | |
10 | Interestingly , RB1 , STK11 , and KEAP1 mutations happened in an almost mutually exclusive way . | ||
11 | These data suggest that LCNEC might represent an evolutionary trunk that can branch to SCLC or AD/SQ , and also that LNETs and non-LNETs are not completely different entities . | ||
12 | This is already suggested by the fact that one of the resistance mechanisms of EGFR-mutant adenocarcinomas to tyrosine - kinase inhibitors is through trans-differentiation to SCLC ( Ref3 ) . | ||
13 | Μ | Finally , we also identified new targetable driver genes in SCLC and LCNEC : FGFR1 amplifications were observed in 6% and 18% of the cases respectively ; PTEN mutations were identified in 10% of the SCLC cases ; and interestingly , one of the LCNEC samples ( belonging to the SCLC-like group ) harboured an activating RFWD2-NTRK1 fusion gene suggesting that fusions affecting NTRK1 may not only be a targetable opportunity for AD ( Ref4 ) but also for LCNEC and , based on the molecular similarities , also SCLC.(1) Peifer and Fernandez-Cuesta et al . | |
14 | Nat Genetics 2012(2) The Clinical Lung Cancer Genome Project ( CLCGP ) and Network Genomic Medicine ( NGM ) Sci Transl Med 2013(3) Sequist et al. , Sci Transl Med 2011(4) Vaishnavi et al . |
PMID: AACR_2016-1386 (Patient) Terms: retrospective |
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0 | Clinical research results for a NGS-based kit for targeted detection of clinically relevant gene rearrangements in lung tumor samples . | ||
1 | In recent years , advances in next-generation sequencing ( NGS ) technologies have enabled faster and cheaper methods for uncovering the genetic basis of disease . | ||
2 | For cancer , NGS based screening for known tumor subtypes may inform diagnosis and allow the clinician to tailor a specific therapeutic approach in the future . | ||
3 | Here , we present the testing results of one such NGS based kit used to detect specific chromosomal translocations in retrospective non-small cell lung cancer ( NSCLC ) samples by targeting specific breakpoints in known fusion transcripts . | ||
4 | The included panel tested consists of a single primer pool containing amplicon designs to simultaneously screen for over 75 specific rearrangements involving the receptor tyrosine kinase ( RTK ) genes ALK , RET and ROS1 as well as NTRK1 . | ||
5 | The panel was compatible with formalin-fixed paraffin-embedded ( FFPE ) lung tumor research samples and achieved high-sensitivity down to 10 ng of RNA input . | ||
6 | In addition , amplicon assays designed at the 5 and 3 ends the RTK genes provide non-specific evidence that a translocation exists in a sample by comparing expression imbalance between the two ends . | ||
7 | Testing was carried out at three external clinical research laboratories . | ||
8 | In addition to positive and negative control samples , each site contributed FFPE lung tumor research samples for which ALK fusion status was known prior to NGS library preparation carried out using the Ion AmpliSeq workflow . | ||
9 | For site -specific samples ( n = 144 , 16 samples per sequencing run ) , high concordance , sensitivity and specificity were measured at 97.2% , 90.5% and 98.4% , respectively . |
PMID: AACR_2016-1392 (Cell) Terms: in vitro |
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0 | Development of highly multiplexed , whole process reference materials for monitoring oncology RNA fusions . | ||
1 | Introduction : Genomic structural alterations are increasingly actionable for targeted therapeutics and personalized medicine . | ||
2 | Μ | Next-generation sequencing methods are increasingly used to detect these fusion RNAs in FFPE material . | |
3 | However , quality control materials for these assays are lacking , and validation materials for rare fusions are frequently not available . | ||
4 | We developed a novel FFPE Fusion RNA Reference Material to fill this unmet need . | ||
5 | Μ | Methods : Highly multiplexed RNAs were designed which contain multiple fusion targets observed predominantly in solid tumors including ALK , RET , ROS1 FGFR3 , and NTRK1 fusions as well as PAX-PPARG fusion and ETV6-NTRK3 fusion . | |
6 | These RNAs were transcribed in vitro and contained a 5 guanosine cap and a poly-adenosine tail to improve intracellular stability . | ||
7 | The RNA was introduced into GM24385 reference cell line ( The 1000 Genomes Project , Coriell ) . | ||
8 | After recovery from transfection , the cells were collected and fixed in formalin . | ||
9 | Digital PCR with TaqMan chemistry was used to determine the average number of synthetic RNA transcripts per cell . | ||
10 | These transfected cells were then mixed with non-transfected GM24385 cells to achieve a consistent low positive , formulation . | ||
11 | The cell mixture was embedded in a paraffin block and 10 micron sections were produced . | ||
12 | Quality control was performed by extracting RNA and testing using the ArcherDx FusionPlex Lung Thyroid Panel and the Ion AmpliSeq RNA Fusion Lung Cancer Research Panel . | ||
13 | Μ | Results : All twelve ( 12 ) fusions present in the prototype were detected as high confidence calls on the ArcherDx Lung Thyroid panel . | |
14 | Whereas embedded cell lines ( with genomic mutations ) give extremely high positive results ( typical results are thousands of reads across the fusion junction ) , Seraseq FFPE Fusion RNA Reference material gave low positive results , similar to patient samples . | ||
15 | The reads spanning the fusion junction ranged from 38 to 396 . | ||
16 | The Ion AmpliSeq RNA Fusion Lung Cancer panel assays only 6 of the fusions in the Seraseq reference material due to their assay design ; however , all assayed fusions were appropriately detected . | ||
17 | Conclusions : Highly multiplexed reference materials in FFPE format are needed for quality control of NGS-based detection of oncology RNA fusions . | ||
18 | Seraseq FFPE RNA Fusion Reference Material allows simultaneous evaluation of detection for twelve fusions observed in a variety of solid tumors , both common and rare . | ||
19 | It generates low positive results on two leading assays , and this is important to truly challenge the assay system and verify performance at levels expected for patient samples . |
PMID: AACR_2017-1009 (None) Terms: |
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0 | Comprehensive ctDNA sequencing reveals mechanisms of resistance to rociletinib in EGFR T790M-mutated NSCLC. . | ||
1 | Background : First and second-generation EGFR tyrosine kinase inhibitors ( TKIs ) have benefited patients with EGFR-mutated non-small cell lung cancer ( NSCLC ) , but resistance invariably develops after a median of 9-16 months . | ||
2 | In ~60% of patients , resistance is mediated by a second mutation in EGFR , namely T790M . | ||
3 | Hence , third-generation EGFR TKIs such as osimertinib and rociletinib were developed to target both activating EGFR mutations as well as T790M . | ||
4 | Unfortunately , patients also develop resistance to these therapies through mechanisms that have not yet been thoroughly explored . | ||
5 | Since repeat tissue biopsies pose potential complications from invasive procedures , circulating tumor DNA ( ctDNA ) testing is increasingly used in the clinical setting to identify potentially targetable mechanisms of resistance . |
PMID: AACR_2016-2266 (Patient) Terms: retrospective |
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0 | Molecular and genomic characterization of SCLC . | ||
1 | Introduction : Small cell lung cancer ( SCLC ) , strongly tobacco-associated , has been described to have a heavy mutation burden , harboring high rates of TP53 and RB1 alterations . | ||
2 | While initially responsive to radiation and chemotherapy , SCLC is characterized by eventual progression and resistance to traditional therapy . | ||
3 | Μ | We retrospectively analyzed a molecular profiling ( MP ) database to identify potentially actionable alterations using a multi-platform approach which includes massively parallel sequencing . | |
4 | Experimental Procedures : SCLC patient samples were referred to a central CLIA laboratory ( Caris Life Sciences , AZ ) for MP ( immunohistochemistry [IHC] and next generation sequencing [NGS] ) . | ||
5 | Expression of PD1 ( MRQ-22 , 1+ ) on tumor infiltrating lymphocytes ( TILs ) and PDL1 ( 130021 , SP142 , 2+5% ) in tumor cells was performed by IHC . | ||
6 | Additional IHC ( ERCC1 , TOPO1 ) and NGS on 591 genes was performed on FFPE samples using the Illumina NextSeq platform in a subset of patient samples . | ||
7 | Μ | All variants were detected with > 99% confidence . | |
8 | Variants are described as follows : pathogenic , presumed pathogenic , variants of unknown significance and unclassified variants ( excluding SNPs ) . | ||
9 | Results : 203 SCLC samples were identified , 48% were females ( 97 ) and 52% were males ( 106 ) . | ||
10 | Median age was 65 [range : 29-88] . | ||
11 | Cancer cells expressed PDL1 in 2.5% of cases ( 5/203 ) and PD1+ TILs were detected in 38% ( 75/197 ) . | ||
12 | For comparison , internal PDL1+ in non-small cell lung carcinomas ( NSCLC ) was 31% ( 339/1098 ) . | ||
13 | Notable findings from IHC included ERCC1 negative status in 93% ( 14/15 ) and TOPO1 + in 70% ( 14/20 ) . | ||
14 | Μ | CNV and mutational analysis ( NGS ) was available for 10 and 22 patients , respectively . | |
15 | Μ | Amplifications were found in the following genes : CCND3 , CRKL , FGF4 , FGFR1 and NFKB1A ( n = 1 , respectively ) , and CCND1 , CCNE1 , CDKN2A and FGF3 ( n = 2 , respectively ) . | |
16 | Μ | As previously reported , the most frequently altered genes were TP53 ( 73% ) and RB1 ( 68% ) . | |
17 | Μ | Clinically relevant pathogenic or presumed pathogenic variants included : EGFR ( exon 19 deletion ) , BRAF (G469A) , APC ( T1556fs ) , NF1 ( A1610fs , D699fs ) , NOTCH1 ( E473fs , C332Y , G546X ) and PTCH1 ( N1351fs ) . | |
18 | It was thought the patient with EGFR mutation is a case of NSCLC transformation to SCLC . | ||
19 | Μ | Variants with unknown significance or unclassified variants detected in genes with clinical relevance and of potential interest for targeted therapy in SCLC include : DDR2 , cMET , RET , FGFR1/3 , BRCA2 , IGF1R , RICTOR and NTRK1 . | |
20 | Conclusion : Genomic and molecular characterization of SCLC samples reveals a heterogeneous population . | ||
21 | Several potentially actionable targets are identified by NGS . | ||
22 | Early reported trial data suggests susceptibility of SCLC to immune checkpoint inhibitors . | ||
23 | Μ | We observed higher levels of PD1+ TILs , however differences in antibody clones , thresholds or staining localization ( tumor cells vs. stromal lymphocytes ) , may account for the observed overall low PD-L1 expression . | |
24 | Further efforts are needed to identify and validate new therapeutic targets in SCLC . |
PMID: AACR_2015-788 (Cell) Terms: xenograft, Xenograft, mice |
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0 | A novel , potent and selective pan-Trk inhibitor ONO-5390556 , demonstrates therapeutic efficacy in cancer cells harboring the TrkA rearrangement . | ||
1 | Purpose : Fusion genes including EML4-ALK , which have been recognized as driver mutations in cancers , encode chimeric proteins with constitutive kinase activity , which promote tumor cell survival . | ||
2 | Μ | Patients with ALK-Positive Non-Small Cell Lung Cancer have demonstrated remarkable clinical responses to the ALK tyrosine kinase inhibitor , Crizotinib . | |
3 | TrkA/NTRK1 , TrkB/NTRK2 and TrkC/NTRK3 belong to the neurotrophic tyrosine kinase receptor family . | ||
4 | Signals from Trk receptors play a role in neuronal survival and differentiation through several signal cascades . | ||
5 | Recently , oncogenic rearrangements of TrkA , B and C genes were identified in a variety of cancers , including lung adenocarcinoma , colorectal cancer , glioblastoma and acute myeloid leukemia . | ||
6 | Therefore , the oncogenic Trk fusion proteins are attractive therapeutic targets that warrant further investigation . | ||
7 | ONO-5390556 is a novel , potent and selective pan-Trk inhibitor with an IC50 in the low nM range . | ||
8 | We evaluated the anti-tumor activity of ONO-5390556 against TrkA rearranged cancer cells in vitro and in vivo . | ||
9 | Methods : Phospho-proteins were detected by Western blotting . | ||
10 | In a proliferation assay , cells were treated with ONO-5390556 at concentrations ranging from 0.03 to 100 nM for 72h . | ||
11 | Cell viability was determined by WST-8 assay . | ||
12 | In a KM12 xenograft model , cells were implanted subcutaneously into female nude mice . | ||
13 | Mice were randomized when the mean tumor volume was 100-200 mm3 . | ||
14 | ONO-5390556 was administered orally with doses ranging between 0.1 and 1 mg/kg twice daily ( BD ) for 14 days . | ||
15 | Tumor volumes were measured twice a week after initiation of treatment , and tumor volumes were determined using the formula volume ( = width2 x length ) /2 . | ||
16 | Results : ONO-5390556 inhibited TrkA autophosphorylation and cell proliferation in BaF3 murine pro B cell lines transformed with a TrkA fusion gene with an IC50 of 0.4 and 0.2 nM , respectively . | ||
17 | Similarly , in KM12 , human colorectal cancer cell lines harboring TPM3-TrkA fusions , both the autophosphorylation of TrkA and the cell proliferation were strongly inhibited by ONO-5390556 with an IC50 of 0.2 and 0.3 nM , respectively . | ||
18 | Interestingly , TrkA autophosphorylation remained strongly inhibited even 24 hours after a washout of ONO-5390556 in KM12 , which suggests ONO-5390556 has tight-binding properties . | ||
19 | In the KM12 Xenograft model , treatment with ONO-5390556 at doses of 0.1 , 0.3 and 1mg ( BD ) for 14 days resulted in a dose -dependent inhibition of tumor growth with Tumor Growth Inhibition ( TGI ) of 48.0 , 89.2 and 95.6% , respectively . | ||
20 | Conclusion : ONO-5390556 is a highly potent and selective pan-Trk inhibitor with evidence of an excellent anti-tumor activity in cancer cells harboring the TrkA rearrangement . | ||
21 | These preliminary results suggest that ONO-5390556 may be an effective therapeutic option in a wide variety of cancers including lung and colorectal cancers with Trk rearrangements . |