AFINITOR is a once-daily oral inhibitor of mTOR (mammalian target of rapamycin) for patients with advanced renal cell carcinoma (RCC) whose disease has progressed on or after treatment with VEGF-targeted therapy
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Angiogenesis
mTOR activation promotes angiogenesis
mTOR plays a key role in angiogenesis — the formation of new blood vessels that provide oxygen and nutrients to growing tumour cells.1-3 Specifically, mTOR controls the production of proteins that play a role in mediating the expression of a wide variety of genes whose products play a role in angiogenesis as well as in cell metabolism, proliferation, motility, adhesion and survival.1-3
In many cancers, angiogenesis is deregulated. Angiogenesis deregulation has been shown to correlate with increased mortality in a number of tumor types, including cervical cancer, breast cancer, non-small-cell lung cancer, ovarian cancer, head and neck cancer and gastrointestinal stromal tumors.3 In addition, loss of the von Hippel-Lindau (VHL) protein is a primary cause of many cases of advanced renal cell carcinoma.4,5
Recently, activated mTOR has been shown in vitro and in animal models to up-regulate production of a key inducer of lymphangiogenesis (VEGF-C).6 In cancer, lymphangiogenesis has been shown to play a causal role in lymph node metastasis. Inhibition of mTOR has been shown to significantly suppress lymph node metastasis in animal models.6
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References
1. Pouysségur J, Dayan F, Mazure N. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441:437-443.
2. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Disc. 2006;5:671-688.
3. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721-731.
4. Ohh M, Kaelin WG. VHL and kidney cancer. Methods Mol Biol. 2003;222:167-183.
5. Hammel PR, Vilgrain V, Terris B, et al. Pancreatic involvement in von Hippel-Lindau disease. Gastroenterology. 2000;119:1087-1095.
6. Kobayashi S, Kishimoto T, Kamata S, Otsuka M, Miyazaki M, Ishikura H. Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci. 2007;98:726-733.
