Study of Met Inhibitors

Mesenchymal-epithelial transition (Met) tyrosine kinase is the receptor for hepatocyte growth factor (HGF), which is normally active in wound healing, liver regeneration, and embryonic development. However, the Met pathway is one of the most frequently dysregulated pathways in human cancer. Met dysregulation leads to constitutive activation of its tyrosine kinase activity thus increasing the downstream signals that lead to cell survival, proliferation, and migration. Patients with upregulated Met tend to have aggressive, chemo-resistant cancers and poor prognoses. For these reasons, the pharmaceutical industry has expended much time and effort to identify potential Met tyrosine kinase inhibitors as potential therapeutics for these cancers.

POTENTIAL THERAPEUTICS

 Crizotinib
The drug Crizotinib has been discussed previously in its role as an EML4-ALK inhibitor for treating non-small cell lung carcinoma. However, Crizotinib is also a Met-inhibitor and shows promise in several other forms of histological cancer associated with Met-dysregulation.

Foretinib
Foretinib is an inhibitor of both Met and vascular endothelial growth factor receptor (VEGFR). Foretinib completed Phase I clinical trials in 2010 and showed potential in treating aggressive solid tumors. Phase II clinical trials are currently underway testing its efficacy in both lung and breast cancer.

Cabozantinib
Like foretinib, Cabozantinib inhibits both Met and VEGFR. It was granted orphan drug status by the FDA in 2011. The orphan drug status is available to encourage pharmaceutical companies to develop drugs for diseases, known as orphan diseases, which have a small market because they are relatively rare. Orphan drugs proceed through their development along the same regulatory pathways as other drugs with the exception that some statistical burdens may be lessened in recognition of the limited patient pool. Furthermore, other financial incentives are also linked to orphan drugs such as tax incentives and extended patent protection. These exceptions are in place to encourage the pharmaceutical industry to develop drugs for these rare diseases, which, by definition, would have a small market share and be relatively unprofitable.

Cabozanitib is currently in clinical trials for treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, hepatocellular, kidney, and medullary thyroid cancer.

SUMMARY

The Met tyrosine kinase is one of the most dysregulated pathways in many cancers. The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit in multiple types of cancer. Therefore, for more than two decades, investigators have been exploring Met inhibitors as potential cancer treatments. Three drugs currently in development are crizotinib, foretinib, and cabozantinib, all of which are currently in early phase clinical trials for treatment of several different cancers. Met inhibitors may prove to be a targeted type therapy with reduced toxicity, that are effective at halting metastasis and improving prognosis in many types of previously resistant tumors.

REFERENCES

1. Porter, J (February 2010), "Small molecule c-Met kinase inhibitors: a review of recent patents", Expert opinion on therapeutic patents 20 (2): 159–177,
2. Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang XY, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JRJ, Cherrington JM, Mendel DB (November 2003), "A selective small molecule inhibitor of c-Met kinase inhibits c-Met dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo", Cancer Research 63 (21): 7345–55,
3. Underiner TL, Herbertz T, Miknyoczki SJ (January 2010), "Discovery of Small Molecule c-Met Inhibitors: Evolution and Profiles of Clinical Candidates", Anti-cancer Agents in Medicinal Chemistry 10 (1): 7–27,
4. Sattler M, Salgia R (April 2009), "The Met axis as a therapeutic target", Update on Cancer Therapeutics 3 (3): 109–118,
5. Christensen JG, Burrows J, Salgia R. (Screening Libraries), "c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention", Cancer Letters 225 (1): 1–26,
6. Qian, F; Engst, S; Yamaguchi, K; Yu, P; Won, KA; Mock, L; Lou, T; Tan, J et al. (2009). "Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases". Cancer research 69 (20): 8009–16.
7. Illingworth, Patricia; Cohen, Jillian (2004). "Orphan Drug Policies: Implications for the United States, Canada, and Developing Countries". Health Law Journal 12: 183.

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