Traditional immunotherapy for renal cell carcinoma (RCC) is being supplanted by new medications that target the biology of kidney cancer. Based on demonstrated efficacy, 3 of these novel agents have now been approved for advanced disease.
The poor outcomes associated with both of these cytokine medications, along with their negative side-effect profiles, have spurred research into novel agents that target the biology of kidney cancer. These agents target a variety of effectors of the von Hippel-Lindau (VHL) pathway, which takes center stage in the pathogenesis of kidney cancer. The figure on page s11 delineates the cellular targets of these new therapies for advanced kidney cancer. Though novel agents are primarily the province of medical oncologists, practicing urologists need to know which of their patients with advanced kidney cancer may benefit from them.
The VHL pathway
Mammalian target of rapamycin (mTOR), a central controller of cell growth that mediates signals from nutrients that pass into the cell and activated growth factor receptors, also promotes increased HIF-1α production. And overproduction of HIF-1α activates production of growth factors that fuel cancer cell growth, neovascularization, and angiogenesis. One of the major targets of HIF-1α is vascular endothelial growth factor (VEGF). Elevated VEGF expression is common in clear-cell kidney cancer and is responsible for the highly vascularized nature of these tumors.
Agents that inhibit kidney tumor angiogenesis
Several clinical trials have tested agents that inhibit vascularization of kidney tumors.
Targeting the VEGF ligand. Based on knowledge of the biology of clear-cell kidney cancer and the role of VHL-mediated gene expression, Yang and colleagues at the National Cancer Institute conducted a double-blind, randomized phase II study of low-dose bevacizumab (Avastin), high-dose bevacizumab, and placebo in previously treated patients with advanced kidney cancer.1 Bevacizumab is a humanized monoclonal antibody that binds circulating VEGF. Compared with patients who received placebo, those who were given high-dose bevacizumab demonstrated a significantly longer time to disease progression (4.8 vs. 2.5 months). These results signal that anti-VEGF directed therapy might have activity in advanced kidney cancer.