Novel therapies for metastatic renal cell carcinoma: efforts to expand beyond the VEGF/mTOR signaling paradigm

Abstract

With six agents approved for metastatic renal cell carcinoma (mRCC) within the past 5 years, there has undoubtedly been progress in treating this disease. However, the goal of cure remains elusive, and the agents nearest approval (i.e., axitinib and tivozanib) abide by the same paradigm as existing drugs (i.e., inhibition of VEGF or mTOR signaling). The current review will focus on investigational agents that diverge from this paradigm. Specifically, novel immunotherapeutic strategies will be discussed, including vaccine therapy, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade, and programmed death-1 (PD-1) inhibition, as well as novel approaches to angiogenesis inhibition, such as abrogation of Ang/Tie-2 signaling. Pharmacologic strategies to block other potentially relevant signaling pathways, such as fibroblast growth factor receptor or MET inhibition, are also in various stages of development. Although VEGF and mTOR inhibition have dramatically improved outcomes for patients with mRCCs, a surge above the current plateau with these agents will likely require exploring new avenues.

Figure 1

Current and future therapeutic strategies for metastatic renal cell carcinoma (mRCC). Boxes in red highlight strategies currently under investigation.

Figure 2

Mechanism of BMS-936558 and tremelimumab/ipilimumab. BMS-936558 binds to PD-1, blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This thereby prevents induction of T-cell anergy and theoretically promotes the antitumor immune response. Tremelimumab and ipilimumab block the interaction between CTLA4 and B7, thereby facilitating T-cell proliferation.