Neoadjuvant Umbrella Trial Directed by Next Generation Sequencing for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations (Without EGFR Sensitizing Mutations)

This umbrella trial directed by next generation sequencing (NGS) includes patients with treatment-naive unresectable stage III non-small-cell lung cancer (NSCLC). The aim of the umbrella study is to evaluate the efficacy of induction NGS-directed targeted therapies followed by surgery for stage III NSCLC patients whose tumor harbors a rare mutation.

Start Date01 Dec 2024

Sponsor / Collaborator

Sun Yat-Sen University

100 Clinical Results associated with MST1R x c-Met

100 Translational Medicine associated with MST1R x c-Met

0 Patents (Medical) associated with MST1R x c-Met

175

Literatures (Medical) associated with MST1R x c-Met

01 Dec 2024·Cellular and Molecular Life Sciences

Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer

Article

Author: Wahoski, Claudia C ; Liu, Qi ; Ayers, Gregory D ; Joshi, Neeraj ; Graves-Deal, Ramona ; Bogatcheva, Galina ; Harmych, Sarah J ; Cao, Zheng ; Jones, Vivian Truong ; Irudayam, Maria Johnson ; Singh, Bhuminder ; Sharma, Vineeta ; Roland, Joseph T ; Janetka, James W ; Higginbotham, James N ; Ramirez, Marisol A ; Damalanka, Vishnu C ; Coffey, Robert J

AbstractAlthough amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC.

01 Oct 2024·Cell Biochemistry and Function

TYRO3 and EPHA2 Expression Are Dysregulated in Breast Cancer

Article

Author: Filho, José Luiz de Lima ; Ferreira, Nancy Cristina Ferraz de Lucena ; Filho, Darley de Lima Ferreira ; Borba, Maria Amelia Carlos Souto Maior ; Mattos, Luiz Alberto ; Leitão, Glauber Moreira ; Martins, Danyelly Bruneska Gondim ; de Aguiar, Ananda Cristina Fernandes

ABSTRACTReceptor tyrosine kinases (RTKs) are involved in cell growth, motility, and differentiation. Deregulation of RTKs signaling is associated with tumor development and therapy resistance. Potential RTKs like TAM (TYRO3, AXL, MERTK), RON, EPH, and MET have been evaluated in many cancers like lung, prostate, and colorectal, but little is known in breast tumors. In this study, 51 luminal breast cancer tissue and 8 triple negative breast cancer (TNBC) subtypes were evaluated by qPCR for the expression of TAM, RON, EPHA2, and MET genes. Statistical analysis was performed to determine the correlation to clinical data. TYRO3 is related to tumor subtype and stage, patient's age, smoking habits, and obesity. MET expression is correlated to EPHA2 and TAM gene expression. EPHA2 expression is also related to aging and smoking habits. The expression levels of the TAM and EPHA2 genes seem to play an important role in breast cancer, being also influenced by the patient's lifestyle.

01 Oct 2023·Acta Biomaterialia

Nanoparticles targeting Sialyl-Tn for efficient tyrosine kinase inhibitor delivery in gastric cancer

Article

Author: Aguiar, Paulo ; Freitas, Daniela ; Gomes, Joana ; Sarmento, Bruno ; Lamas, Sofia ; Osório, Hugo ; Diniz, Francisca ; Gärtner, Fátima ; Reis, Celso A

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide and, therefore, it is urgent to develop new and more efficient therapeutic approaches. Foretinib (FRT) is an oral multikinase inhibitor targeting MET (hepatocyte growth factor receptor) and RON (recepteur d'origine nantais) receptor tyrosine kinases (RTKs) that has been used in clinical trials for several solid tumors. Targeted uptake of therapeutic polymeric nanoparticles (NPs) represents a powerful approach in cancer cell drug delivery. Previously, a nanodelivery system composed of polymeric NPs functionalized with B72.3 antibody, which targets the tumor-associated antigen Sialyl-Tn (STn), has been developed. Herein, these NPs were loaded with FRT to evaluate its capacity in delivering the drug to multicellular tumors spheroids (MCTS) and mouse models. The data indicated that B72.3 functionalized FRT-loaded PLGA-PEG-COOH NPs (NFB72.3) specifically target gastric MCTS expressing the STn glycan (MKN45 SimpleCell (SC) cells), leading to a decrease in phospho-RTKs activation and reduced cell viability. In vivo evaluation using MKN45 SC xenograft mice revealed that NFB72.3 were able to decrease tumor growth, reduce cell proliferation and tumor necrosis. NFB72.3-treated tumors also showed inactivation of phospho-MET and phospho-RON. This study demonstrates the value of using NPs targeting STn for FRT delivery, highlighting its potential as a therapeutic application in GC. STATEMENT OF SIGNIFICANCE: Despite the advances in gastric cancer therapeutics, it remains one of the diseases with the highest incidence and mortality in the world. Combining targeted therapies with a controlled drug release is an attractive strategy to reduce drug cytotoxic effects and improve specific drug delivery efficiency to the cancer cells. Thus, we developed nanoparticles loaded with a tyrosine kinase inhibitor and targeting a specific tumor glycan exclusive of cancer cells. In in vivo gastric cancer xenograft mice models, these nanoparticles efficiently reduced tumor growth, cell proliferation and tumor necrosis area and inactivated phosphorylation of targeting receptors. This approach represents an innovative therapeutic strategy with high impact in gastric cancer.

News (Medical) associated with MST1R x c-Met

29 May 2012

·www.biospace.com

MethylGene to Present MGCD265 Data at the 2012 American Society of Clinical Oncology Annual Meeting

Montreal, Canada. May 29, 2012 – MethylGene Inc. (TSX:MYG) today announced that clinical data for its Met/VEGF-R kinase inhibitor, MGCD265, will be presented at the 2012 ASCO Annual Meeting to be held in Chicago, Illinois from June 1 to 5, 2012. This poster presentation will highlight the safety pro MGCD265 when used as a monotherapy in this ongoing dose-escalation study. Poster Presentation MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR: Dose-escalation Phase I study. Date and Time: Monday June 4, 8:00 AM to 12:00 PM (CT) Session: Developmental Therapeutics - Experimental Therapeutics Abstract No.: 3039 Location: S Hall A2 About MGCD265 MGCD265 is a novel, oral small molecule inhibitor that targets a unique spectrum of receptor tyrosine kinases: Met, VEGFR 1, 2, and 3, Tie-2 and Ron. These kinases play key roles in tumor development, survival and metastasis as well as the inappropriate formation of blood vessels (angiogenesis) that nourish the tumor. MGCD265 has completed one Phase 1 single agent study, and is nearing completion of one Phase 1 single agent clinical trial and one Phase 1/2 combination clinical trial (with erlotinib and docetaxel) in solid tumors. About MethylGene MethylGene Inc. (TSX:MYG) is a small molecule drug development company that is advancing two novel therapeutics for cancer and infectious disease in human clinical trials. The Company’s lead product candidates are: MGCD290, an oral antifungal agent targeting the fungal Hos2 enzyme that is currently in Phase 2 trials for vulvovaginal candidiasis, and MGCD265, an oral Met/VEGF receptor kinase inhibitor that is in Phase 1/2 clinical trials for solid tumor cancers. MethylGene owns all rights to its lead product candidates, and has partnerships with Otsuka Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., and EnVivo Pharmaceuticals, Inc. for its other pipeline programs. Investor Relations Contact: Joseph Walewicz, CFA Vice President, Business & Corporate Development MethylGene Inc. Phone: 514-337-3333 ext. 373 ir@methylgene.com Thomas Fechtner Vice President The Trout Group LLC Phone: 646-378-2931 tfechtner@troutgroup.com

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