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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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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: Cancer J Clin. 2019;69:7–34. Wiley.

    PubMed  Google Scholar 

  2. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer Cancer. 2010;116:4256–65.

    Article  CAS  PubMed  Google Scholar 

  3. Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer Pergamon. 2013;49:1287–96.

    Article  CAS  Google Scholar 

  4. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24. Massachusetts Medical Society.

    Article  CAS  PubMed  Google Scholar 

  5. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.

    Article  CAS  PubMed  Google Scholar 

  6. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–23. Massachusetts Medical Society.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet (London, England). 2011;378:1931–9 (Elsevier).

    Article  CAS  PubMed  Google Scholar 

  8. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–1127. https://doi.org/10.1056/NEJMoa1816714.

  9. Motzer RJ, Tannir NM, McDermott DF, ArénFrontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289–300. Massachusetts Medical Society.

    Article  CAS  PubMed  Google Scholar 

  11. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829–41. Massachusetts Medical Society.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. •• Choueiri TK, Kaelin WG. Targeting the HIF2–VEGF axis in renal cell carcinoma. Nature Medicine 2020 26:10. Nature Publishing Group; 2020;26:1519–30. High-level overview of the scientific rationale for the development of HIF-2α inhibition in metastatic renal cell carcinoma.

  13. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Ren Physiol. 2006;291:271–81. American Physiological Society.

    Article  Google Scholar 

  14. Yu T, Tang B, Sun X. Development of inhibitors targeting hypoxia-inducible factor 1 and 2 for cancer therapy. Yonsei Med J. 2017;58:489–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bratslavsky G, Sudarshan S, Neckers L, Linehan WM. Pseudohypoxic pathways in renal cell carcinoma. Clin Cancer Res. 2007;13:4667–71. American Association for Cancer Research.

    Article  CAS  PubMed  Google Scholar 

  16. Loboda A, Jozkowicz A, Dulak J. HIF-1 versus HIF-2 — Is one more important than the other? Vasc Pharmacol. 2012;56:245–51 (Elsevier).

    Article  CAS  Google Scholar 

  17. Cho H, Kaelin WG. Targeting HIF2 in clear cell renal cell carcinoma. Cold Spring Harb Symp Quant Biol. 2016;81:113–21. Cold Spring Harbor Laboratory Press.

    Article  PubMed  Google Scholar 

  18. Linehan WM, Ricketts CJ. The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol. 2019;16:9. Nature Publishing Group; 2019;16:539–52.

    Article  Google Scholar 

  19. Choi WSW, Boland J, Lin J. Hypoxia-inducible factor-2α as a novel target in renal cell carcinoma. J Kidney Cancer VHL. 2021;8:1. Codon Publications.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhang C, Li L, Zhang Y, Zeng C. Hereditary leiomyomatosis and renal cell cancer: recent insights into mechanisms and systemic treatment. Frontiers in oncology [Internet]. Front Oncol; 2021 [cited 2021 Jul 14];11. Available from: https://pubmed.ncbi.nlm.nih.gov/34113573/

  21. Chittiboina P, Lonser RR. Von Hippel–Lindau disease. Handbook of Clinical Neurology. Elsevier; 2015;132:139–56.

  22. Makhov P, Joshi S, Ghatalia P, Kutikov A, Uzzo RG, Kolenko VM. Resistance to systemic therapies in clear cell renal cell carcinoma: mechanisms and management strategies. Mol Cancer Ther. 2018;17:1355–64. American Association for Cancer Research.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, et al. Genetic and functional studies implicate HIF1a as a 14q kidney cancer suppressor gene. Cancer Disc. 2011;1:222–35. American Association for Cancer Research.

    Article  CAS  Google Scholar 

  24. Raval RR, Lau KW, Tran MGB, Sowter HM, Mandriota SJ, Li J-L, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol. 2005;25:5675–86. American Society for Microbiology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Biswas S, Troy H, Leek R, Chung Y-L, Li J-L, Raval RR, et al. Effects of HIF-1α and HIF2α on growth and metabolism of clear-cell renal cell carcinoma 786–0 xenografts. J Oncol. 2010;2010:14. Hindawi Publishing Corporation.

    Article  Google Scholar 

  26. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, et al. HIF-a effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell. 2008;14:435–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Koehler AN. A complex task? Direct modulation of transcription factors with small molecules. Curr Opin Chem Biol. 2010;14:331. NIH Public Access.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martínez-Sáez O, GajateBorau P, Alonso-Gordoa T, Molina-Cerrillo J, Grande E. Targeting HIF-2 α in clear cell renal cell carcinoma: a promising therapeutic strategy. Critical reviews in oncology/hematology. Crit Rev Oncol Hematol. 2017;111:117–23.

    Article  PubMed  Google Scholar 

  29. Keefe SM, Hoffman-Censits J, Cohen RB, Mamtani R, Heitjan D, Eliasof S, et al. Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I-IIa clinical trial. Ann Oncol. 2016;27:1579. Oxford University Press.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, et al. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α. Mol Cancer Ther. 2008;7:90–100. American Association for Cancer Research.

    Article  CAS  PubMed  Google Scholar 

  31. Tanaka T, Yamaguchis J, Shojis K, Nangakus M. Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host. J Biol Chem. 2012;287:34866–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharma Sin B. 2015;5:378–89.

    Article  Google Scholar 

  33. Rogers JL, Bayeh L, Scheuermann TH, Longgood J, Key J, Naidoo J, et al. Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor. J Med Chem. 2013;56:1739–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2a antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36:867–74. American Society of Clinical Oncology.

    Article  CAS  PubMed  Google Scholar 

  35. Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, et al. 3-[(1 S,2 S,3 R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a hypoxia-inducible factor 2α (HIF-2α) inhibitor for the treatment of clear cell renal cell carcinoma. J Med Chem. 2019;62:6876–93. American Chemical Society.

    Article  CAS  PubMed  Google Scholar 

  36. Binderup MLM, Galanakis M, Budtz-Jørgensen E, Kosteljanetz M, Bisgaard ML. Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark. Eur J Hum Genet. 2017;25:301. Nature Publishing Group.

    Article  CAS  PubMed  Google Scholar 

  37. Pilié P, Hasanov E, Matin SF, Woodson AHH, Marcott VD, Bird S, et al. Pilot study of dovitinib in patients with von Hippel-Lindau disease. Oncotarget Impact J. 2018;9:23390–5.

    Article  Google Scholar 

  38. Oudard S, Elaidi R, Brizard M, Rest CL, Caillet V, Deveaux S, et al. Sunitinib for the treatment of benign and malignant neoplasms from von Hippel-Lindau disease: a single-arm, prospective phase II clinical study from the PREDIR group. Oncotarget Impact J. 2016;7:85306–17.

    Article  Google Scholar 

  39. Jonasch E, McCutcheon IE, Gombos DS, Ahrar K, Perrier ND, Liu D, et al. Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol. 2018;19:1351–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. •• Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N Engl J Med. Massachusetts Medical Society; 2021;385:2036–46. This study of belzutifan in VHL-associated RCC and other VHL-associated neoplasms resulted in the approval of belzutifan in this setting.

  41. Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27:802. NIH Public Access.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Choueiri TK, Albiges L, Fan L, Perini RF, Zojwalla NJ, Powles T, et al. Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC). Am Soc Clin Oncol. 2020;38:TPS5094–TPS5094. https://doi.org/10.1200/JCO20203815_supplTPS5094.

    Article  Google Scholar 

  43. Zhou X, Hou W, Gao L, Shui L, Yi C, Zhu H. Synergies of antiangiogenic therapy and immune checkpoint blockade in renal cell carcinoma: from theoretical background to clinical reality. Front Oncol. 2020;10:1321. Frontiers Media S.A.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K, et al. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J Hematol Oncol. 2022;15:77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hsu T-S, Lin Y-L, Wang Y-A, Mo S-T, Chi P-Y, Lai AC-Y, et al. HIF-2α is indispensable for regulatory T cell function. Nat Commun. 2020;11:5005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xiong Y, Liu L, Xia Y, Qi Y, Chen Y, Chen L, et al. Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma. Cancer Immunol Immunother. 2019;68:731–41.

    Article  CAS  PubMed  Google Scholar 

  47. Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, et al. Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible factor-2 alpha, is regulated by von Hippel-Lindau gene mutation status. Eur Urol. 2016;70:623–32.

    Article  CAS  PubMed  Google Scholar 

  48. Han G, Stevens C, Cao Z, Xie S, Maddie M, Goggin B, et al. Abstract 4022: PT2385, a novel HIF-2α antagonist, combines with checkpoint inhibitor antibodies to inhibit tumor growth in preclinical models by modulating myeloid cells and enhancing T cell infiltration. Can Res. 2016;76:4022.

    Article  Google Scholar 

  49. Rini BI, Appleman LJ, Figlin RA, Plimack ER, Merchan JR, Wang K, et al. Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC. Proc Am Soc Clin Oncol. 2019;37:558–558. https://doi.org/10.1200/JCO2019377_suppl558.

    Article  Google Scholar 

  50. Choueiri TK, Bauer TM, McDermott DF, Arrowsmith E, Roy A, Perini RF, et al. Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). Proc Am Soc Clin Oncol. 2021;39:272–272. https://doi.org/10.1200/JCO2021396_suppl272.

    Article  Google Scholar 

  51. McDermott DF, Choueiri TK, Bauer TM, Arrowsmith E, Roy A, Perini RF, et al. Phase II study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, plus cabozantinib for treatment of advanced clear cell renal cell carcinoma (ccRCC). Ann Oncol [Internet]. 2021;32 (suppl_5). Available from: https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/phase-ii-study-of-belzutifan-mk-6482-an-oral-hypoxia-inducible-factor-2a-hif-2a-inhibitor-plus-cabozantinib-for-treatment-of-advanced-clear-c. Accessed 29 Jul 2022.

  52. National Cancer Institute. Definition of belzutifan - NCI Drug Dictionary - NCI [Internet]. 2011 [cited 2022 Dec 26]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/belzutifan. Accessed 29 Jul 2022.

  53. National Cancer Institute. Definition of HIF2alpha inhibitor DFF332 - NCI Drug Dictionary - NCI [Internet]. 2011 [cited 2022 Dec 26]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/hif2alpha-inhibitor-dff332. Accessed 29 Jul 2022.

  54. • Brugarolas J, Beckermann K, Rini BI, Vogelzang NJ, Lam ET, Hamilton JC, et al. Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). Proc Am Soc Clin Oncol. 2022;40:339–339. https://doi.org/10.1200/JCO2022406_suppl339. This is the first study of RNA interference (RNAi) as a possible mechanism for HIF-2α inhibition.

    Article  Google Scholar 

  55. Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer. 2016;139:396–403.

    Article  CAS  PubMed  Google Scholar 

  56. Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375:2246–54. Massachusetts Medical Society.

    Article  CAS  PubMed  Google Scholar 

  57. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang Y-H, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385:683–94. Massachusetts Medical Society.

    Article  CAS  PubMed  Google Scholar 

  58. Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, et al. On-target efficacy of a HIF2α antagonist in preclinical kidney cancer models. Nature. 2016;539:107. NIH Public Access.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. • Courtney KD, Ma Y, de Leon AD, Christie A, Xie Z, Woolford L, et al. HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clin Cancer Res. American Association for Cancer Research Inc.; 2020;26:793–803. This article described potential mechanisms of resistance to HIF-2α inhibition.

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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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