Drug Targets for Renal Cancer

Drug Targets C-Raf, B-Raf for Renal Cancer with Approved Drugs

Drug target Cancer drugs Company
c-Raf Sorafenib Bayer and Onyx Pharmaceuticals
b-Raf Sorafenib Bayer and Onyx Pharmaceuticals

Sorafenib is an orally administered bi-aryl urea that was designed originally as an inhibitor of B-Raf and C-Raf, non-receptor serine threonine kinases. These kinases are members of the Raf/MEK/ERK intracellular signaling cascade, a downstream effector of Ras, which in turn can be activated by upstream receptor TK stimulation. Activation of the Raf/MEK/ERK cascade leads to changes in metabolism, transcription, and intracellular cytoskeletal arrangements. This pathway is known to be involved in tumor cell survival and proliferation and is a therapeutic target in cancer, such as renal cancer. (Larkin JM, Eisen T. Renal cell carcinoma and the use of sorafenib. Therapeutics and Clinical Risk Management. 2006;2(1):87-98.)

Drug Targets VEGF/VEGFR for Renal Cancer with Approved Drugs

Drug targets Cancer drugs Company
VEGFR-1, VEGFR-2, VEGFR-3 Sunitinib Bayer and Onyx Pharmaceuticals
VEGFR-1, VEGFR-2, VEGFR-3 Pazopanib GlaxoSmithKline
VEGFR-1, VEGFR-2, VEGFR-3 Axitinib Pfizer
VEGFR-2 Cabozantinib Ipsen
VEGFR-1, VEGFR-2, VEGFR-3 Lenvatinib Eisai Co.
VEGF Bevacizumab Roche

Several treatment strategies have been investigated in metastatic renal cancer. One approach is to block the signals initiated by angiogenic growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor. VEGF is the major factor responsible for tumor angiogenesis, and there is a particularly strong rationale for blocking VEGF in renal cancer. Approximately 60% of clear cell renal cancer tumors have an inactivated von-Hippel Lindau (VHL) tumor suppressor gene, either through somatic mutation (∼50% of RCC tumors) or promoter methylation (∼10% of tumors). A normal VHL protein indirectly represses transcription of hypoxia-inducible genes, such as VEGF, by targeting the α subunit of hypoxia-inducible factor-α for proteolytic degradation. Under hypoxic conditions or when the VHL gene is inactivated, hypoxia-inducible factor-α is not degraded, resulting in induction of VEGF transcription, overexpression of VEGF protein, and angiogenesis.

Drug Targets mTOR for Renal Cancer with Approved Drugs

Drug target Cancer drugs Company
mTOR Temsirolimus Wyeth Pharmaceuticals
mTOR Everolimus Novartis

The mTOR pathway may be of particular relevance to renal cancer as it has been shown that HIF protein expression is dependent on mTOR in certain cellular contexts. Inappropriate accumulation of HIF-1α and HIF-2α as a result of biallelic alterations in the von Hippel-Lindau (VHL) gene observed in the majority of clear cell renal cancer is believed to be a critical step in renal cancer tumorigenesis as a result of increased expression of HIF-regulated gene products including VEGF, PDGF and TGF-α. Toschi et al. have shown that mTOR activation, in conjunction with the presence of phospholipase D, enhances the expression of both HIF-1α and HIF-2α in renal cancer cells at a translational level rather than transcriptional. Furthermore, treatment of mice bearing renal cancer xenograft models with temsirolimus has been shown to result in impaired expression of HIF-1α under both hypoxic and normoxic conditions, presenting another potential mechanism of action for the rapalogs in patient with renal cancer. (Battelli C, Cho DC. mTOR inhibitors in renal cell carcinoma. Therapy. 2011;8(4):359-367.)

Drug Targets PD-1 for Renal Cancer with Approved Drugs

Drug target Cancer drugs Company
PD-1 Nivolumab Bristol-Myers Squibb

The interaction between programmed death-1 (PD-1, present on T cells), and one of its ligands (PD-L1, present on antigen-presenting cells and tumor cells) constitutes an immune checkpoint through which tumors can induce T-cell tolerance and avoid immune destruction. Monoclonal antibodies that disrupt the PD-1/PD-L1 interaction serve as inhibitors of this immune checkpoint, and have demonstrated favorable activity in renal cancer as monotherapy and in combination with other active agents. (Weinstock M, McDermott D. Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma. Therapeutic Advances in Urology. 2015;7(6):365-377.)

Drug targets for Renal cancer: Related Information