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Targeting HIF-2 Alpha in Renal Cell Carcinoma

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Opinion Statement

Current treatment options for patients with metastatic renal cell carcinoma (mRCC) are limited to immunotherapy with checkpoint inhibitors and targeted therapies that inhibit the vascular endothelial growth factor receptors (VEFG-R) and the mammalian target of rapamycin (mTOR). Despite significantly improved outcomes over the last few decades, most patients with mRCC will ultimately develop resistance to these therapies, thus highlighting the critical need for novel treatment options. As part of the VHL–HIF–VEGF axis that rests at the foundation of RCC pathogenesis, hypoxia-inducible factor 2α (HIF-2α) has been identified as a rationale target for mRCC treatment. Indeed, one such agent (belzutifan) is already approved for VHL-associated RCC and other VHL-associated neoplasms. Early trials of belzutifan indicate encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan and other HIF-2α inhibitors into the mRCC treatment armamentarium either as a single agent or as combination therapy would be a welcome addition for patients with mRCC.

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  1. Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI, 53226, USA

    Ramsha Ahmed MD

  2. Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave, CA-60, Cleveland, OH, 44195, USA

    Moshe C. Ornstein MD, MA

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Dr. Ramsha Ahmed has nothing to disclose. Dr. Moshe C. Ornstein has served in consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol Myers Squibb; served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, Astra-Zeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis - all outside the submitted work.

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Ahmed, R., Ornstein, M.C. Targeting HIF-2 Alpha in Renal Cell Carcinoma. Curr. Treat. Options in Oncol. 24, 1183–1198 (2023). https://doi.org/10.1007/s11864-023-01106-y

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