Hypoxia-Inducible Factor-2α as a Novel Target in Renal Cell Carcinoma
Main Article Content
Keywords
clear cell renal cell carcinoma, HIF-2α inhibitors, hypoxia-inducible factor, pseudohypoxia, von Hippel–Lindau)
Abstract
Hypoxia-inducible factor (HIF), an important mediator of hypoxia response, is implicated in tumorigenesis in the setting of pseudohypoxia, such as in the inactivation of von Hippel–Lindau tumor suppressor protein (pVHL), leading to development and progression of clear cell renal cell carcinoma (ccRCC). Targeting downstream molecules in HIF pathway, such as vascular endothelial growth factor (VEGF), has led to improvement in clinical outcome for patients with advanced ccRCC, but such therapy thus far has been limited by eventual resistance and treatment failure. Following the discovery of HIF-2α playing a key role in ccRCC carcinogenesis, inhibitors targeting HIF-2α have been developed and have demonstrated encouraging efficacy and safety profile in clinical trials. This review discusses HIF-2α as a promising therapeutic target for ccRCC.
References
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22. 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-2 alpha transcription factor. J Med Chem. 2013;56(4):1739–47. https://doi.org/10.1021/jm301847z
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24. Courtney KD, Ma Y, Diaz de Leon A, 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. 2020;26(4):793–803. https://doi.org/10.1158/1078-0432.CCR-19-1459
25. Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzo nitrile (PT2977), a hypoxia-inducible Factor 2 alpha (HIF-2 alpha) inhibitor for the treatment of clear cell renal cell carcinoma. J Med Chem. 2019;62(15):6876–93. https://doi.org/10.1021/acs.jmedchem.9b00719
2. Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, et al. Improved identification of von Hippel–Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14(15):4726–34. https://doi.org/10.1158/1078-0432.CCR-07-4921
3. Loughlin KR. Hypoxia inducible factor (HIF): Its central role in renal cell cancer targeted therapy. Urol Oncol. 2009;27(3):236–7. https://doi.org/10.1016/j.urolonc.2008.08.006
4. Yu T, Tang B, Sun X. Development of inhibitors targeting hypoxia-inducible Factors 1 and 2 for cancer therapy. Yonsei Med J. 2017;58(3):489–96. https://doi.org/10.3349/ymj.2017.58.3.489
5. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol. 2006;291(2):F271–81. https://doi.org/10.1152/ajprenal.00071.2006
6. Loboda A, Jozkowicz A, Dulak J. HIF-1 versus HIF-2 -- Is one more important than the other? Vascul Pharmacol. 2012;56(5–6):245–51. https://doi.org/10.1016/j.vph.2012.02.006
7. Hu CJ, Sataur A, Wang L, Chen H, Simon MC. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha. Mol Biol Cell. 2007;18(11):4528–42. https://doi.org/10.1091/mbc.e06-05-0419
8. Bratslavsky G, Sudarshan S, Neckers L, Linehan WM. Pseudohypoxic pathways in renal cell carcinoma. Clin Cancer Res. 2007;13(16):4667–71. https://doi.org/10.1158/1078-0432.CCR-06-2510
9. Toledo RA. New HIF2alpha inhibitors: Potential implications as therapeutics for advanced pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2017;24(9):C9–19. https://doi.org/10.1530/ERC-16-0479
10. Cho H, Kaelin WG. Targeting HIF2 in clear cell renal cell carcinoma. Cold Spring Harb Symp Quant Biol. 2016;81:113–21. https://doi.org/10.1101/sqb.2016.81.030833
11. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1 alpha and HIF-2 alpha to common target genes is differentially regulated in neuroblastoma: HIF-2 alpha promotes an aggressive phenotype. Cancer Cell. 2006;10(5):413–23. https://doi.org/10.1016/j.ccr.2006.08.026
12. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, 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(13):5675–86. https://doi.org/10.1128/MCB.25.13.5675-5686.2005
13. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23(24):9361–74. https://doi.org/10.1128/MCB.23.24.9361-9374.2003
14. Biswas S, Troy H, Leek R, Chung YL, Li JL, Raval RR, et al. Effects of HIF-1 alpha and HIF2 alpha on growth and metabolism of clear-cell renal cell carcinoma 786-0 xenografts. J Oncol. 2010;2010:757908. https://doi.org/10.1155/2010/757908
15. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, et al. Genetic and functional studies implicate HIF1 alpha as a 14q kidney cancer suppressor gene. Cancer Discov. 2011;1(3):222–35. https://doi.org/10.1158/2159-8290.CD-11-0098
16. Keith B, Johnson RS, Simon MC. HIF1 alpha and HIF2 alpha: Sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12(1):9–22. https://doi.org/10.1038/nrc3183
17. 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(7):1355–64. https://doi.org/10.1158/1535-7163.MCT-17-1299
18. Chittiboina P, Lonser RR. Von Hippel–Lindau disease. Handb Clin Neurol. 2015;132:139–56. https://doi.org/10.1016/B978-0-444-62702-5.00010-X
19. 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(10):1351–9. https://doi.org/10.1016/S1470-2045(18)30487-X
20. Jonasch E, McCutcheon IE, Waguespack SG, Wen S, Davis DW, Smith LA, et al. Pilot trial of sunitinib therapy in patients with von Hippel–Lindau disease. Ann Oncol. 2011;22(12):2661–6. https://doi.org/10.1093/annonc/mdr011
21. 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-2 alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36(9):867–74. https://doi.org/10.1200/JCO.2017.74.2627
22. 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-2 alpha transcription factor. J Med Chem. 2013;56(4):1739–47. https://doi.org/10.1021/jm301847z
23. Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112–7. https://doi.org/10.1038/nature19796
24. Courtney KD, Ma Y, Diaz de Leon A, 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. 2020;26(4):793–803. https://doi.org/10.1158/1078-0432.CCR-19-1459
25. Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzo nitrile (PT2977), a hypoxia-inducible Factor 2 alpha (HIF-2 alpha) inhibitor for the treatment of clear cell renal cell carcinoma. J Med Chem. 2019;62(15):6876–93. https://doi.org/10.1021/acs.jmedchem.9b00719
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Apr 7, 2021
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How to Cite
Hypoxia-Inducible Factor-2α as a Novel Target in Renal Cell Carcinoma. (2021). Journal of Kidney Cancer, 8(2), 1-7. https://doi.org/10.15586/jkcvhl.v8i2.170
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Kidney Cancer: Original Articles
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How to Cite
Hypoxia-Inducible Factor-2α as a Novel Target in Renal Cell Carcinoma. (2021). Journal of Kidney Cancer, 8(2), 1-7. https://doi.org/10.15586/jkcvhl.v8i2.170