c-Met is a proto-oncogene responsible for encoding the high-affinity receptor for hepatocyte growth factor (HGF).
Hepatocyte growth factor is also known as scatter factor which participates in HGF/c-MET signaling pathway. This pathway plays vital role in mitogenesis and morphogenesis during embryonic development and wound healing.
The controlled natural activity of c-Met and HGF is important in mammalian development, tissue maintenance, and repair. Binding of HGF to c-MET receptor induces several biological responses collectively known as invasive growth program.
These responses are elicited due to activation of several pathways such as RAS pathway, PI3K pathway, STAT pathway, beta-catenin pathway and Notch pathway. However, dysregulation of the HGF/c-MET signaling pathway has been associated with the progression of cancers through activation of oncogenic pathways, angiogenesis and metastasis.
c-Met kinase represents a novel target for cancer therapy and several research institutes and pharmaceuticals companies are engaged in developing new oncology drugs based on this inhibition of HGF or c-Met-dependent signaling pathway. Number of approaches being attempted to target c-Met include: c-Met biologic inhibitors, small molecule c-Met inhibitors, HGF antagonist antibodies, c-Met antagonist antibodies (MetMAb) and HGF kringle variant antagonists.
A study undertaken by University of Heidelberg, Heidelberg, Germany demonstrated therapeutic potential of cabozantinib (Exelixis, Inc., Phase III) for against pancreatic ductal adenocarcinoma (PDA) and this molecule induced low-level of resistance compared to gemcitabine.
The major cancers such as breast, colon and non-small-cell lung carcinoma (NSCLC) are being examined for efficacy with c-MET / HGF inhibitors. Several small molecule c-Met kinase inhibitors have demonstrated clinical efficacy in cancer treatment and many clinical trials are underway.
However, as the small molecule inhibitors lack specificity or selectivity they can cause toxicity. Therefore, researchers are increasing focus to develop antibody therapeutics against c-Met or HGF.
Several drugs are in developmental stage and underway clinical trials in various phases of clinical trials. Some of the prominent molecules include ARQ 197 (Arcule, Inc., Phase II), AV-299 (AVEO Pharmaceuticals, Inc., Phase II), cabozantinib (Exelixis, Inc., Phase III), JNJ-38877605 (Johnson & Johnson), PF04217903 (Pfizer, Inc., Phase I), PF02341066 (Pfizer, Inc., Phase II), GSK1363089 (GlaxoSmithKline plc), MK-2461 (Merck & Co., Phase II), MP470 (SuperGen, Inc., Phase I), and MGCD265 (Methylgene, Inc., Phase I), AMG102 (Amgen, Inc., Phase II), HuL2G7 (Galaxy Biotech, LLC) and MetMAb (Genentech, Inc., Phase I).
The global c-MET / HGF inhibitors market is yet to establish and hence every company is trying to expedite the research and development activity along with clinical trials. The larger multinationals are collaborating with companies having intellectual property rights but suffer from an insufficient capacity to commercialize the molecules.
For instance, AstraZeneca signed a licensing deal with Hutchison MediPharma Ltd., to develop volitinib (HMPL-504/AZD6094) in non-small-cell lung carcinoma (NSCLC). Another recent development in the market was AVEO Oncology entering into a worldwide agreement with Biodexis in which latter company’s companion diagnostic test will be commercialized with AVEO’s ficlatuzumab (HGF inhibitory antibody).
Some of the companies having presence in the global c-MET / HGF inhibitors market are Abxign, Inc., Abbott Laboratories, Amgen, Inc., ArQule, Inc., Astex Therapeutics Ltd., AVEO Pharmaceuticals, Inc., Bristol-Myers Squibb (BMS) Co., Chroma Therapeutics Ltd., Daiichi Sankyo Co. Ltd., Deciphera Pharmaceuticals, LLC, Eisai Co., Ltd., Eli Lilly and Co., Exelixis, Inc., Genmab A/S, Galaxy Biotech, LLC, GlaxoSmithKline (GSK) plc, Hutchison MediPharma Ltd., Johnson & Johnson, Kringle Pharmaceuticals, Inc., Merck & Co., Methylgene, Inc., Novartis AG, Pfizer, Inc., ProMetic BioTherapeutics, Inc., and Takeda Pharmaceutical Co.
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