title: Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy.
abstract: 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 α (HIF-α) accumulates inside the tumor cell and dimerizes with HIF-β. The HIF-α/HIF-β complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2α subunit has a central role in ccRCC over HIF-1α. 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-2α with HIF-1β. 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-2α 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-2α inhibitors in ccRCC and give an overview of the development of new agents in this setting.
authors.affiliation: Medical Oncology Department, Ramon y Cajal University Hospital, Ctra, Colmenar Viejo km9100, 28029, Madrid, Spain. Electronic address: olgamarsa@hotmail.com.
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Sáez
authors.affiliation: Medical Oncology Department, Ramon y Cajal University Hospital, Ctra, Colmenar Viejo km9100, 28029, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Gajate Borau
authors.affiliation: Medical Oncology Department, Ramon y Cajal University Hospital, Ctra, Colmenar Viejo km9100, 28029, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Alonso-Gordoa
authors.affiliation: Medical Oncology Department, Ramon y Cajal University Hospital, Ctra, Colmenar Viejo km9100, 28029, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Molina-Cerrillo
authors.affiliation: Medical Oncology Department, Ramon y Cajal University Hospital, Ctra, Colmenar Viejo km9100, 28029, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Grande
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019281:Dimerization; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007189:Indans; D013450:Sulfones; D000099162:Endothelial PAS Domain-Containing Protein 1; C000614279:PT2385; C000614278:PT2399
keywords: Angiogenesis; HIF; HIF-2α inhibitors; Renal cell carcinoma