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cMET
cMET cMET(1)
c-Met is a protooncogene that encodes hepatocyte growth factor (HGF) receptor.(247) It is a membrane receptor, essential for embryonic development and wound healing. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces invasive growth.(247) MET engagement activates multiple signal transduction pathways: Abnormal MET activation in cancer correlates with poor prognosis, and aberrantly active MET triggers tumor growth, angiogenesis, and metastasis. MET is deregulated in many types of human malignancies, including RCC, HCC, stomach, BC, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells appear to hijack the ability of normal stem cells to express MET. MET pathway plays an important role in the development of cancer through: (i) activation of key oncogenic pathways (RAS, PI3K, STAT3, -catenin); (ii) angiogenesis; and (iii) scatter (cells dissociation due to metalloprotease production), which often leads to metastasis.(247)


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References

1. CD37. [cited]; Available from: http://en.wikipedia.org/wiki/CD37.

2. Abounader R RT, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J. Regulation of c-Met-dependent gene expression by PTEN. Oncogene. 2004;23(57):9173-82. PMCID: 15516982.

3. Gude NA EG, Wu W, Cottage CT, Fischer K, Quijada P, Muraski JA, Alvarez R, Rubio M, Schaefer E, Sussman MA. Activation of Notch-mediated protective signaling in the myocardium. Circ Res. 2008;102(9):1025-35. PMCID: 18369158.

4. Gentile A TL, Comoglio PM. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 2008;27(1):85-94. PMCID: 18175071.

5. Boccaccio C AM, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature. 1998;391(6664):285-8. PMCID: 9440692.

6. Monga SP MW, Pediaditakis P, Bell A, Mulé K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002;7(62):2064-71. PMCID: 11929826.

7. O'Brien LE TK, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE. ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. Dev Cell. 2004;7(1):21-32. PMCID: 15239951.

8. CJ M. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995;80(2):179-85. PMCID: 7834738.

9. Graziani A GD, Cantley LC, Comoglio PM. The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. J Biol Chem. 1991;266(33):22087-90. PMCID: 1718989.



News
Monday, October 10, 2016 3:24 PM|Rosen, L. S., Goldman, J. W., Algazi, A. P., Turner, P. K., Moser, B., Hu, T., Wang, X. A., Tuttle, J., Wacheck, V., Wooldridge, J. E., Banck, M.|Clinical Cancer Research Online First Articles|Labels: EGFR, MET, clinical trial

Purpose: The MET/hepatocyte growth factor (HGF) pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here we report dose escalation results from the first-in-human phase I trial of emibetuzumab. Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered IV every two weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended Phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1400, and 2000 mg and fourteen NSCLC patients at 700, 1400, and 2000mg in combination with erlotinib 150mg daily. No dose-limiting toxicities, related serious or {greater than or equal to} grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear pharmacokinetics at doses >210mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700-2000 mg IV Q2W.

Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, VEGF, liver cancer, clinical trial
The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, VEGF, prostate cancer
This pilot clinical trial studies cabozantinib in treating men with hormone-resistant prostate cancer. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
Wednesday, August 31, 2016 8:00 PM|Kang, Y.-K.|The Oncologist Subject Collection: Gastrointestinal Cancer|Labels: MET, esophageal cancer, biomarker diagnostic, clinical trial
Background.The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined. Patients and Methods.Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression-free survival (PFS) in intent-to-treat (ITT) and MET-positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET-positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Results.Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval [CI], 0.71-1.63; p = .71). In the MET-positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60-3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64-1.75; p = .83). In the MET-positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45-2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3-5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively. Conclusion.The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population. Implications for PracticeThe YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: MET, liver cancer, lung cancer, biomarker diagnostic, clinical trial
Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted.Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent M...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: MET, VEGF, lung cancer, clinical trial
Conclusions: The RP2D of Cabo in Japanese pts was determined to be 60 mg. The safety and pharmacokinetic profiles are consistent with data from studies in non-Japanese pts. Antitumor activity with Cabo has been observed, including in pts with molecularly-defined NSCLC.Citation Format: Hiroshi Nokihara, Makoto Nishio, Noboru Yamamoto, Yutaka Fujiwawa, Hidehito Horinouchi, Shintaro Kanda, Asushi Horiike, Fumiyoshi Ohyanagi, Yifah Yaron, Anne Borgman, Tomohide Tamura. Final results of a phase 1 study of cabozantinib (Cabo) in Japanese patients (pts) with expansion cohorts in non-small cell lung cancer (NSCLC) with defined molecular alterations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Phila...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, MET, lung cancer, clinical trial
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7.Citation Format: Giorgio V. Scagliotti, Sergey Orlov, Joachim von Pawel, Frances A. Shepherd, Wallace Akerley, Jeffrey S. Ross, Dale Shuster, Qiang Wang, Brian Schwartz, Reinhard von Roemeling. Tivantinib in combination with erlotinib vs erlotinib alone for EGFR mutant NSCLC: Subgroup results from the phase 3 MARQUEE study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(1...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: MET, VEGF, prostate cancer, clinical trial
Several kinase inhibitors targeting aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in early phase clinical trials, particularly in cancer patients with bone metastases. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with increased neutrophil chemotactic factor expression, including CXCL12 and HMGB1 production by tumor cells, and robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutrali...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, MET, mTOR, lung cancer
Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression in multiple cancer types, including non-small cell lung cancer (NSCLC), where the cMET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here, we explore the therapeutic potential of the potent and selective cMET inhibitor savolitinib (volitinib, AZD6094, HMPL-504) in NSCLC and begin to elucidate mechanisms of acquired savolitinib resistance in preclinical models. Using in vitro proliferation assays and immunoblot analysis, we determine that savolitinib rapidly inhibits cMET auto-phosphorylation/activation and reduces t...
Wednesday, January 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, FAK, MET
In this study, we explored ceritinib-resistant mechanisms using ceritinib-resistant, echinoderm microtubule-associated protein-like 4-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. Genetic alteration was examined by sequencing of cancer related genes. Protein expression related to ceritinib was examined by receptor-tyrosine kinase (RTK) array, immunoblotting and IHC. To overcome the identified resistance, single or combination treatment of the kinase inhibitors was testes in vitro and in vivo.We identified three novel ceritinib resistance mechanisms: a resistance mutation (L1198F), fibroblast growth factor receptor 3 (FGFR3) activation, and cMET gene amplification. L1198F-mutated ALK was the most sensitive to crizotinib. Molecular dynamic structure simulation succe...

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Saturday, June 18, 2016 1:15 AM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: MET, mTOR, VEGF, kidney cancer
Patients with advanced or metastatic renal cell carcinoma derive a significant overall survival benefit from second-line treatment with the multi-tyrosine kinase inhibitor cabozantinib relative to everolimus.
Monday, October 10, 2016 5:26 AM|Cancer News -- ScienceDaily|Labels: MET, VEGF, kidney cancer
Cabozantinib significantly improves progression-free survival and response rate in patients with metastatic renal cell carcinoma compared to sunitinib, according to research.
Saturday, June 18, 2016 2:05 PM|Bernard Escudier; Thomas Powles; Nizar M Tannir; Paul N Mainwaring; Brian I Rini; Hans J Hammers; Frede Donskov; Bruce J Roth; Katriina Peltola; Jae Lyun Lee; Daniel Y C Heng; Manuela Schmidinger; Neeraj Agarwal; Cora N Sternberg; David F McDermott; Dana T Aftab; Colin Hessel; Christian Scheffold; Gisela Schwab; Thomas E Hutson; Sumanta Pal; Robert J Motzer|JournalTOCs API - The Lancet Oncology (50 articles)|Labels: MET, mTOR, VEGF, kidney cancer, clinical trial

Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial
Toni K Choueiri Bernard Escudier; Thomas Powles; Nizar M Tannir; Paul N Mainwaring; Brian I Rini; Hans J Hammers; Frede Donskov; Bruce J Roth; Katriina Peltola; Jae Lyun Lee; Daniel Y C Heng; Manuela Schmidinger; Neeraj Agarwal; Cora N Sternberg; David F McDermott; Dana T Aftab; Colin Hessel; Christian Scheffold; Gisela Schwab; Thomas E Hutson; Sumanta Pal; Robert J Motzer
The Lancet Oncology, Vol. 17, No. 7 (2016) pp. 917 - 927
Publication date: Available online 5 June 2016 Source:The Lancet Oncology Author(s): Toni K Choueiri, Bernard Escudier, Thomas Powles, Nizar M Tannir, Paul N Mainwaring, Brian I Rini, Hans J Hammers, Frede Donskov, Bruce J Roth, Katriina Peltola, Jae Lyun Lee, Daniel Y C Heng, Manuela Schmidinger, Neeraj Agarwal, Cora N Sternberg, David F McDermott, Dana T Aftab, Colin Hessel, Christian Scheffold, Gisela Schwab, Thomas E Hutson, Sumanta Pal, Robert J Motzer Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p<0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.

Wednesday, October 12, 2016 3:26 PM|Joohyuk Sohn, Shuying Liu, Napa Parinyanitikul, Jangsoon Lee, Gabriel N. Hortobagyi, Gordon B. Mills, Naoto T. Ueno, Ana M. Gonzalez-Angulo|Journal of Cancer|Labels: EGFR, MET, breast cancer

Background: EGFR expression and pathway activation are common in triple-negative breast cancer (TNBC). However, anti-EGFR therapies have not been effective in these patients. We aimed to study the efficacy of targeting MET in overcoming resistance to EGFR therapy in TNBC cell lines.

Methods: TNBC lines (MDA-MB-468, HCC-1395, and MDA-MB-231), and a hormone receptor-positive breast cancer line (T47D) were stimulated with epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Lines were then treated with different concentrations of EGFR inhibitors (gefitinib or cetuximab), with or without a MET tyrosine kinase inhibitor (EMD 1214063). Proliferation was measured by MTS assay, in soft agar and with a matrigel assay. Synergy was measured with Calcusyn. Protein expression and signaling were examined with immunoblotting.

Results: There was activation of ligand-receptor-downstream signaling pathways in MDA-MB-468 and HCC-1395 upon stimulation with EGF and HGF. In these cell lines, we observed synergism when combining EGFR and MET inhibitors. These results were observed across assays. In western blotting, combination therapy resulted in abrogation of pAKT and pMAPK while monotherapy did not.

Conclusion: Our data demonstrate that dual EGFR/MET inhibition is synergistic in TNBC. Targeting both EGFR and MET receptors may provide an effective therapeutic strategy in TNBC.

Sunday, August 14, 2016 5:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: MET, RAS, VEGF, thymic, clinical trial
CONCLUSIONSThese data suggest that cabozantinib provides the greatest clinical benefit to patients with MTC who have RET M918T or RAS mutations. However, a prospective trial is needed to confirm the relation between genetic variation and the response to cabozantinib. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, September 14, 2016 4:57 AM|PBR - Regulatory Affairs News|Labels: MET, VEGF
The European Commission (EC) has approved Cabometyx (cabozantinib) tablets to treat advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy.
Cabometyxâ„¢ (cabozantinib) is the first and only targeted therapy to improve Overall Survival (OS), Objective Response Rate (ORR), and Progression Free Survival (PFS) in RCC in METEOR randomized Ph...
Sunday, October 9, 2016 7:00 PM|PBR - News|Labels: MET, VEGF, clinical trial
Biopharmaceutical firm Exelixis has announced results from a phase 1 trial of cabozantinib in combination with nivolumab in patients with previously treated genitourinary tumors.
Monday, October 24, 2016 3:45 AM|Yoshinori Imura, Takaaki Nakai, Shutaro Yamada, Hidetatsu Outani, Satoshi Takenaka, Kenichiro Hamada, Nobuhito Araki, Kazuyuki Itoh, Hideki Yoshikawa, Norifumi Naka|Cancer Science|Labels: MET, sarcoma
Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma with a poor prognosis and thus novel therapeutic strategies for SS are urgently required. In the present study, we investigated functional and therapeutic relevance of hepatocyte growth factor (HGF)/c-MET signaling in SS. Both HGF and c-MET were highly expressed in Yamato-SS cells, resulting in activation of c-MET and its downstream AKT and extracellular signal-regulated kinase signaling pathways, whereas c-MET was expressed but not activated in SYO-1 or HS-SY-II cells. c-MET-activated Yamato-SS cells showed higher anchorage-independent growth ability and less sensitivity to chemotherapeutic agents than did c-MET-inactivated SYO-1 or HS-SY-II cells. INC280, a selective c-MET inhibitor, inhibited growth of Yamato-SS cells both in vitro and in vivo but not that of SYO-1 or HS-SY-II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c-MET and its downstream effectors in Yamato-SS cells. Co-expression of HGF and c-MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c-MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c-MET-activated SS. HGF/c-MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c-MET inhibitors. This article is protected by copyright. All rights reserved.
Friday, July 1, 2016 9:56 AM|Chong, C. R., Bahcall, M., Capelletti, M., Kosaka, T., Ercan, D., Sim, T., Sholl, L. M., Nishino, M., Johnson, B. E., Gray, N. S., Janne, P. A.|Clinical Cancer Research Online First Articles|Labels: ALK, MET, VEGF, lung cancer, regulatory

Purpose: 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. Experimental design: 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. Results: 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 nM, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nM, respectively), entrectinib (IC50 = 6/2,200 /3,500 nM), and PF-06463922 (IC50 = 1/270/2 nM). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924, potently inhibited CD74-NTRK1 transformed compared to parental Ba/F3 cells (IC50 = 19 nM vs. > 470 nM). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response. Conclusions: 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.

Cabozantinib met the primary endpoint of improving progression-free survival as compared to sunitinib, decreasing the rate of disease progression or death by 31 percent Objective response rate sig...
Regulatory News: Ipsen (Euronext: IPN; ADR: IPSEY), a global specialty-driven pharmaceutical group, today announced that Cabometyxâ„¢ (cabozantinib), Somatuline Autogel (lanreotide) and telotristat ...
Wednesday, September 28, 2016 4:00 AM|Merck News Releases|Attachments|Labels: EGFR, MET, clinical trial
Darmstadt, Germany, September 28, 2016 – Merck, a leading science and technology company, today announced that new research from their marketed and pipeline compounds will be presented at this year’s European Society for Medical Oncology (ESMO; October 7–11, 2016, Copenhagen, Denmark) annual meeting. Presentations will focus on hard-to-treat cancers, and include: study results for Erbitux® (cetuximab) in metastatic colorectal cancer (mCRC) and squamous cell carcinoma of the head and neck (SCCHN); preliminary study results in bladder cancer and renal cell carcinoma (RCC) for avelumab, which is being developed in collaboration with Pfizer; and updates on the Phase II program for tepotinib* in non-small cell lung cancer (NSCLC).
Wednesday, October 12, 2016 3:26 PM|Zuoquan Xie, Young H. Lee, Marta Boeke, Lucia B. Jilaveanu, Zongzhi Liu, Donald P. Bottaro, Harriet M. Kluger, Brian Shuch|Journal of Cancer|Labels: AKT, MapK, MET, mTOR, VEGF, kidney cancer

Background: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC.

Methods: An interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed.

Results: Twelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited.

Conclusions: We provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity.

Sunday, May 1, 2016 1:00 AM|Friedlander, Michael L.; Russell, Kenneth; Millis, Sherri; Gatalica, Zoran; Bender, Ryan; Voss, Andreas|International Journal of Gynecological Cancer - Most Popular Articles|Labels: MET, ovarian cancer
imageBackground: Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets. Patients and Methods: Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis. Results: The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%). Conclusions: This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.
Tuesday, October 18, 2016 12:35 PM|Onclive Articles|Labels: MET
Cabozantinib plus nivolumab demonstrated promising activity in the second-line setting and beyond at all dose levels tested in patients with advanced/refractory genitourinary cancers.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, clinical trial
MGCD265 is an orally administered receptor tyrosine kinase inhibitor that targets MET and other receptors. This study is a Phase 2 trial of MGCD265 in patients with locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) that has activating genetic changes of the MET gene (mutation or amplification [increase number of gene copies]). Testing for tumor gene changes can be performed in tumor tissue or blood samples. Patients must have previously received treatment with chemotherapy. The number of patients to be enrolled will depend on how many enrolled patients experience tumor size reduction. MGCD265 will be administered orally, twice daily. The study is designed to evaluate whether the number of patients experiencing tumor size reduction is substantially higher than would be expected with other available treatments.
Monday, October 3, 2016 12:05 AM|Huang, Q., Schneeberger, V. E., Luetteke, N., Jin, C., Afzal, R., Budzevich, M. M., Makanji, R. J., Martinez, G. V., Shen, T., Zhao, L., Fung, K.-M., Haura, E. B., Coppola, D., Wu, J.|Molecular Cancer Therapeutics current issue|Labels: MET, VEGF

RET fusions have been found in lung adenocarcinoma, of which KIF5B–RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B–RET-dependent cell lines for preclinical modeling of KIF5B–RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B–RET expression. By culturing KIF5B–RET-dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RETV804L mutation and vandetanib-resistant-RETG810A mutation. Among cabozantinib, lenvatinib, ponatinib, and vandetanib, ponatinib was identified as the most potent inhibitor against KIF5B–RET and its drug-resistant mutants. Interestingly, the vandetanib-resistant KIF5B-RETG810A mutant displayed gain-of-sensitivity (GOS) to ponatinib and lenvatinib. Treatment of doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice with ponatinib effectively induced tumor regression. These results indicate that KIF5B-RET–associated lung tumors are addicted to the fusion oncogene and ponatinib is the most effective inhibitor for targeting KIF5B–RET in lung adenocarcinoma. Moreover, this study finds a novel vandetanib-resistant RETG810A mutation and identifies lenvatinib and ponatinib as the secondary drugs to overcome this vandetanib resistance mechanism. Mol Cancer Ther; 15(10); 2521–9. ©2016 AACR.

Friday, October 14, 2016 12:05 AM|K.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: MET, thymic

Thyroid Cancer
Raue, F Frank-Raue, K.
Clinical Cancer Research, Vol. 22, No. 20 (2016) pp. 5012 - 5021
Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules. After total thyroidectomy and radioiodine treatment, DTC remains an indolent and curable disease in most patients, whereas the cure rate in MTC is lower and depends on early diagnosis. Most ATCs are incurable. In recent years, there has been great progress in identifying genetic changes in thyroid cancer, and genetic testing of FNA samples or blood samples provides useful information for clinical decision making. Tumor staging, either postoperatively or by imaging, and measuring the tumor markers thyroglobulin for DTC and calcitonin for MTC, allow for dynamic risk-adapted stratification for follow-up procedures. In advanced metastatic thyroid cancer, molecular targeted therapy using tyrosine kinase receptor inhibitors, including sorafenib, lenvantinib, vandetanib, and cabozantinib, helps control tumor progression and prolongs progression-free survival. Using a dynamic risk-stratified approach to manage thyroid cancer, the outcomes for most thyroid cancer patients are excellent compared with those for other cancers. The major challenge in the future is to identify high-risk patients and to treat and monitor them appropriately. Clin Cancer Res; 22(20); 5012&ndash;21. &copy;2016 AACR. See all articles in this CCR Focus section, "Endocrine Cancers: Revising Paradigms."

Friday, October 14, 2016 12:05 AM|Raue, F., Frank-Raue, K.|Clinical Cancer Research recent issues|Labels: MET, VEGF, thymic

Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules. After total thyroidectomy and radioiodine treatment, DTC remains an indolent and curable disease in most patients, whereas the cure rate in MTC is lower and depends on early diagnosis. Most ATCs are incurable. In recent years, there has been great progress in identifying genetic changes in thyroid cancer, and genetic testing of FNA samples or blood samples provides useful information for clinical decision making. Tumor staging, either postoperatively or by imaging, and measuring the tumor markers thyroglobulin for DTC and calcitonin for MTC, allow for dynamic risk-adapted stratification for follow-up procedures. In advanced metastatic thyroid cancer, molecular targeted therapy using tyrosine kinase receptor inhibitors, including sorafenib, lenvantinib, vandetanib, and cabozantinib, helps control tumor progression and prolongs progression-free survival. Using a dynamic risk-stratified approach to manage thyroid cancer, the outcomes for most thyroid cancer patients are excellent compared with those for other cancers. The major challenge in the future is to identify high-risk patients and to treat and monitor them appropriately. Clin Cancer Res; 22(20); 5012–21. ©2016 AACR.

See all articles in this CCR Focus section, "Endocrine Cancers: Revising Paradigms."