Novel Biomarkers in metastatic renal cell carcinoma

During the past decade, basic and translational cancer research has provided new information regarding the mechanisms underlying tumor growth, proliferation, and metastasis in renal cell carcinoma (RCC). Understanding of the molecular pathogenesis of RCC has identified new targets for therapeutic intervention. Angiogenesis, involving complex signaling pathways such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, and angiopoietins, plays a pivotal role in tumor growth and progression, and therapies targeting angiogenic factors from the VEGF family have become an effective strategy in the treatment of metastatic renal-cell carcinoma (mRCC) since 2006. Sunitinib and pazopanib are tyrosine kinase inhibitors (TKI) and they are globally used as first-line treatments for mRCC. Although they primarily act through inhibiting angiogenesis, they might also have an effect on the function of immune cells such as T-regs. Despite the initial enthusiasm for these modern-era targeted therapies, however, some patients only receive moderate benefit, and resistance to these therapies eventually develops in all patients. At present, no biomarkers predicting treatment efficacy are known, despite intensive translational research during the last decade. While the main component of the angiogenic process in RCC is VEGF, targeting of the mammalian target of the rapamycin (mTOR) pathway is important, because activation of the upstream PI3K/Akt/mTOR signaling pathways is one method by which constitutive HIF-1α activation or upregulation occurs. Everolimus is an orally available mTOR inhibitor and is commonly used after TKI treatment failure/intolerance. As with TKI inhibitors, however, there are wide differences in responses to everolimus treatment, and it remains unclear which patients most benefit from the treatment. Our results confirm TKI-induced hypertension (HTN) as a strong predictor of a good prognosis and response among patients treated with sunitinib/pazopanib. We additionally demonstrated that the use angiotensin system inhibitors (ASIs) in the treatment of TKI-induced HTN may have synergistic beneficial effects when used in conjunction with sunitinib or pazopanib. In our investigation of tumor tyrosine protein kinase Met (c-Met) expression and the outcome, we demonstrated that high levels of c-Met expression associate with a worse prognosis among mRCC patients treated with sunitinib. We also demonstrated that high c-Met expression is associated with a poor outcome among patients without bone metastases at baseline, suggesting that the prognostic role may vary depending on the location of the metastases. In our two studies conducted on everolimus-treated patients, we showed that everolimus-induced pneumonitis associates with an improved outcome, suggesting a role as a surrogate marker of the efficacy of everolimus treatment. We additionally confirmed the prognostic value of hyponatremia in a large cohort of everolimus-treated patients.