Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy

The loss of the Von Hippel-Lindau tumor suppressor (VHL) is a key oncogenic event in the vast majority of patients with clear cell renal cell carcinoma (ccRCC). With the loss of the VHL protein (pVHL) function, the hypoxia inducible factor a (HIF-alpha) accumulates inside the tumor cell and dimerizes with HIF-beta. The HIF alpha/HIF-alpha complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2 alpha subunit has a central role in ccRCC over HIF-l alpha Thus, efforts have been made to specifically target this pathway. PT2385 and PT2399 are first-in-class, orally available, small molecule inhibitors of HIF-2 that selectively disrupt the heterodimerization of HIF-2 alpha with HIF-1 beta. Preclinical and clinical data indicate that these new molecules are effective in blocking cancer cell growth, proliferation, and tumor angiogenesis characteristic in ccRCC. Treatment with HIF-2 alpha specific antagonists, either alone or in combination with immunotherapy or other antiangiogenic agents have the potential to transform the therapeutic landscape in this tumor in the future. Herein, we summarize the molecular background behind the use of HIF-2 alpha inhibitors in ccRCC and give an overview of the development of new agents in this setting. (C) 2017 Elsevier B.V. All rights reserved.