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Targeting the HIF2–VEGF axis in renal cell carcinoma

Abstract

Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.

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Fig. 1
Fig. 2: Mechanisms of resistance.

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Acknowledgements

We acknowledge Z. Bakouny and K. Pels (Dana-Farber Cancer Institute) and N. Zojwalla (Peloton Therapeutics) for careful reading of this manuscript and useful suggestions.

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T.K.C. reports receiving research support (institutional and personal) from AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb & Sons, Cerulean, Eisai, Foundation Medicine, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda; honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb & Sons, Cerulean, Eisai, Foundation Medicine, Exelixis, Genentech, Roche, Roche Products, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, Analysis Group, National Comprehensive Cancer Network, Michael J. Hennessy (MJH) Associates (healthcare communications company with several brands, such as OncLive, PeerView and PER), Research to Practice, L-path, Kidney Cancer journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, New England Journal of Medicine, Lancet Oncology, Heron Therapeutics and Lilly; has had a consulting or advisory role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb & Sons, Cerulean, Eisai, Foundation Medicine, Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, National Comprehensive Cancer Network, Analysis Group, Pionyr and Tempest; owns stock in Pionyr and Tempest; and has received travel, accommodations, and expenses in relation to consulting, advisory roles or honoraria. W.G.K. is a board director at Lilly Pharmaceuticals, is a founder of Tango Therapeutics and Cedilla Therapeutics, is a Scientific Advisor at Nextech Invest, has ownership interest (including stock, patents, etc.) in Lilly, Tango Therapeutics, Nextech Invest and Cedilla Therapeutics, and is a consultant/advisory board member for Lilly Pharmaceuticals, Tango Therapeutics, Nextech Invest and Cedilla Therapeutics.

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Choueiri, T.K., Kaelin, W.G. Targeting the HIF2–VEGF axis in renal cell carcinoma. Nat Med 26, 1519–1530 (2020). https://doi.org/10.1038/s41591-020-1093-z

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