Hypoxic stress: Obstacles and opportunities for innovative immunotherapy of cancer

Oncogene

Volumn 36, Issue 4, 2017, Pages 439-445

  Chouaib, S ^a   Noman, M Z ^a   Kosmatopoulos, K ^b   Curran, M A ^c  

^a INSERM   (France)

^b Vaxon Biotech   (France)

^c UNIVERSITY OF TEXAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; CANCER GROWTH; CANCER IMMUNOTHERAPY; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL HETEROGENEITY; CELL PROLIFERATION; CYTOKINE PRODUCTION; HUMAN; HYPOXEMIA; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOSURVEILLANCE; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; STROMA CELL; TUMOR HYPOXIA; TUMOR MICROENVIRONMENT; VASCULARIZATION; ANIMAL; CELL HYPOXIA; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASMS; PROCEDURES;

ANIMALS; CELL HYPOXIA; HUMANS; IMMUNOTHERAPY; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 84976300398     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2016.225     Document Type: Article

References (100)

1. Homet Moreno B, Ribas A. Anti-programmed cell death protein-1/ligand-1 therapy in different cancers. Br J Cancer 2015; 112: 1421-1427.
2. Noman MZ, Messai Y, Carre T, Akalay I, Meron M, Janji B, et al. Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression, antitumor response. Crit Rev Immunol 2011; 31: 357-377.
3. Terry S, Chouaib S. EMT in immuno-resistance. Oncoscience 2015; 2: 841-842.
4. Hamai A, Benlalam H, Meslin F, Hasmim M, Carre T, Akalay I, et al. Immune surveillance of human cancer: if the cytotoxic T-lymphocytes play the music, does the tumoral system call the tune? Tissue Antigens 2010; 75: 1-8.
5. Noman MZ, Benlalam H, Hasmim M, Chouaib S. Cytotoxic T cells-stroma interactions. Bull Cancer 2011; 98: E19-E24.
6. Noman MZ, Chouaib S. Targeting hypoxia at the forefront of anticancer immune responses. Oncoimmunology 2014; 3: e954463.
7. Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B, et al. Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am J Physiol Cell Physiol 2015; 309: C569-C579.
8. Semenza GL. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des 2009; 15: 3839-3843.
9. Semenza GL. Hypoxia-inducible factors in physiology, medicine. Cell 2012; 148: 399-408.
10. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression, targets for cancer therapy. Trends Pharmacol Sci 2012; 33: 207-214.
11. Messai Y, Noman MZ, Hasmim M, Escudier B, Chouaib S. HIF-2alpha/ITPR1 axis: a new saboteur of NK-mediated lysis. Oncoimmunology 2015; 4: e985951.
12. Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, et al. TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol 2005; 174: 7592-7599.
13. Lukashev D, Caldwell C, Ohta A, Chen P, Sitkovsky M. Differential regulation of two alternatively spliced isoforms of hypoxia-inducible factor-1 alpha in activated T lymphocytes. J Biol Chem 2001; 276: 48754-48763.
14. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T (reg) balance by hypoxia-inducible factor 1. Cell 2011; 146: 772-784.
15. Ohta A, Diwanji R, Kini R, Subramanian M, Sitkovsky M. In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front Immunol 2011; 2: 27.
16. Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development, effector functions. J Immunol 2001; 167: 6140-6149.
17. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 2013; 14: 1173-1182.
18. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J, et al. PDK1 regulation of mTOR, hypoxia-inducible factor 1 integrate metabolism, migration of CD8+ T cells. J Exp Med 2012; 209: 2441-2453.
19. Robbins JR, Lee SM, Filipovich AH, Szigligeti P, Neumeier L, Petrovic M, et al. Hypoxia modulates early events in T cell receptor-mediated activation in human T lymphocytes via Kv1.3 channels. J Physiol 2005; 564: 131-143.
20. Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L, et al. Cutting edge: hypoxia-inducible factor 1alpha, its activation-inducible short isoform I.1 negatively regulate functions of CD4+, CD8+ T lymphocytes. J Immunol 2006; 177: 4962-4965.
21. Thiel M, Chouker A, Ohta A, Jackson E, Caldwell C, Smith P, et al. Oxygenation inhibits the physiological tissue-protecting mechanism, thereby exacerbates acute inflammatory lung injury. PLoS Biol 2005; 3: e174.
22. Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P, et al. Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues, improves septic mice survival. PLoS One 2007; 2: e853.
23. Palazon A, Martinez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, et al. The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Disc 2012; 2: 608-623.
24. Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B, Abbott R, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 2015; 7: 277-ra230.
25. Mellor AL, Munn DH. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev 2008; 8: 74-80.
26. Payen VL, Porporato PE, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis, the pentose phosphate pathway. Cell Mol Life Sci 2016; 73: 1333-1348.
27. Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol 2001; 69: 522-530.
28. Nakagawa Y, Negishi Y, Shimizu M, Takahashi M, Ichikawa M, Takahashi H. Effects of extracellular pH, hypoxia on the function, development of antigenspecific cytotoxic T lymphocytes. Immunol Lett 2015; 167: 72-86.
29. Redegeld F, Filippini A, Sitkovsky M. Comparative studies of the cytotoxic T lymphocyte-mediated cytotoxicity, of extracellular ATP-induced cell lysis. Different requirements in extracellular Mg2+, pH. J Immunol 1991; 147: 3638-3645.
30. Ratner S. Lymphocytes stimulated with recombinant human interleukin-2: relationship between motility into protein matrix, in vivo localization in normal, neoplastic tissues of mice. J Natl Cancer Inst 1990; 82: 612-616.
31. Lugini L, Matarrese P, Tinari A, Lozupone F, Federici C, Iessi E, et al. Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res 2006; 66: 3629-3638.
32. Droge W, Roth S, Altmann A, Mihm S. Regulation of T-cell functions by L-lactate. Cell Immunol 1987; 108: 405-416.
33. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007; 109: 3812-3819.
34. Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 1997; 57: 2602-2605.
35. Sitkovsky MV. Damage control by hypoxia-inhibited AK. Blood 2008; 111: 5424-5425.
36. Hoskin DW, Mader JS, Furlong SJ, Conrad DM, Blay J. Inhibition of T cell, natural killer cell function by adenosine, its contribution to immune evasion by tumor cells (Review). Int J Oncol 2008; 32: 527-535.
37. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine generation catalyzed by CD39, CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204: 1257-1265.
38. Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory, primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol 2006; 177: 6780-6786.
39. Lukashev D, Ohta A, Sitkovsky M. Hypoxia-dependent anti-inflammatory pathways in protection of cancerous tissues. Cancer Metastasis Rev 2007; 26: 273-279.
40. Tan S, Zhou F, Nielsen VG, Wang Z, Gladson CL, Parks DA. Sustained hypoxiaischemia results in reactive nitrogen, oxygen species production, injury in the premature fetal rabbit brain. J Neuropathol Exp Neurol 1998; 57: 544-553.
41. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 2007; 13: 828-835.
42. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 2011; 208: 1949-1962.
43. Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxiamediated escape from adaptive immunity in cancer cells. Cancer Res 2014; 74: 665-674.
44. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, , its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014; 211: 781-790.
45. Yamada N, Yamanegi K, Ohyama H, Hata M, Nakasho K, Futani H, et al. Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1alpha-dependent manner. Int J Oncol 2012; 41: 2005-2012.
46. Noman MZ, Janji B, Berchem G, Chouaib S. miR-210, hypoxic microvesicles: two critical components of hypoxia involved in the regulation of killer cells function. Cancer Lett 2015; e-pub ahead of print 30 October 2015; doi:10.1016/j.canlet.2015.10.026.
47. Sarkar S, Germeraad WT, Rouschop KM, Steeghs EM, van Gelder M, Bos GM, et al. Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells. PLoS One 2013; 8: e64835.
48. Sceneay J, Chow MT, Chen A, Halse HM, Wong CS, Andrews DM, et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells, compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res 2012; 72: 3906-3911.
49. Wolter F, Glassner A, Kramer B, Kokordelis P, Finnemann C, Kaczmarek DJ, et al. Hypoxia impairs anti-viral activity of natural killer (NK) cells but has little effect on anti-fibrotic NK cell functions in hepatitis C virus infection. J Hepatol 2015; 63: 1334-1344.
50. Baginska J, Viry E, Berchem G, Poli A, Noman MZ, van Moer K, et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc Natl Acad Sci USA 2013; 110: 17450-17455.
51. Tittarelli A, Janji B, Van Moer K, Noman MZ, Chouaib S. The selective degradation of synaptic Connexin 43 protein by hypoxia-induced autophagy impairs natural killer cell-mediated tumor cell killing. J Biol Chem 2015; 290: 23670-23679.
52. Zhang J, Han C, Dai H, Hou J, Dong Y, Cui X, et al. Hypoxia-inducible factor-2alpha limits natural killer T cell cytotoxicity in renal ischemia/reperfusion injury. J Am Soc Nephrol 2016; 27: 92-106.
53. Noman MZ, Janji B, Kaminska B, Van Moer K, Pierson S, Przanowski P, et al. Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity, promotes regression. Cancer Res 2011; 71: 5976-5986.
54. Noman MZ, Janji B, Berchem G, Mami-Chouaib F, Chouaib S. Hypoxia-induced autophagy: a new player in cancer immunotherapy? Autophagy 2012; 8: 704-706.
55. Noman MZ, Buart S, Romero P, Ketari S, Janji B, Mari B, et al. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res 2012; 72: 4629-4641.
56. Viry E, Baginska J, Berchem G, Noman MZ, Medves S, Chouaib S, et al. Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis. Autophagy 2014; 10: 173-175.
57. Messai Y, Noman MZ, Hasmim M, Janji B, Tittarelli A, Boutet M, et al. ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy. Cancer Res 2014; 74: 6820-6832.
58. Messai Y, Noman MZ, Janji B, Hasmim M, Escudier B, Chouaib S. The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing. Autophagy 2015; e-pub ahead of print 25 February 2015.
59. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, et al. Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance, function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA 2012; 109: E2784-E2793.
60. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17, Treg cells. J Exp Med 2011; 208: 1367-1376.
61. Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation, cancer. J Immunol 2011; 186: 4388-4395.
62. Lee JH, Elly C, Park Y, Liu YC. E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1alpha to maintain regulatory T cell stability, suppressive capacity. Immunity 2015; 42: 1062-1074.
63. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance, angiogenesis via CCL28, T(reg) cells. Nature 2011; 475: 226-230.
64. Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 2012; 167: 195-205.
65. Chafe SC, Dedhar S. Carving out its niche: a role for carbonic anhydrase IX in pre-metastatic niche development. Oncoimmunology 2015; 4: e1048955.
66. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis, invasion. Cancer Cell 2008; 13: 206-220.
67. Lin S, Wan S, Sun L, Hu J, Fang D, Zhao R, et al. Chemokine C-C motif receptor 5, C-C motif ligand 5 promote cancer cell migration under hypoxia. Cancer Sci 2012; 103: 904-912.
68. Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE(2)-induced CXCL12 production, CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res 2011; 71: 7463-7470.
69. Takehara H, Iwamoto J, Mizokami Y, Takahashi K, Ootubo T, Miura S, et al. Involvement of cyclooxygenase-2-prostaglandin E2 pathway in interleukin-8 production in gastric cancer cells. Dig Dis Sci 2006; 51: 2188-2197.
70. Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis, restores antitumor immunity. Cancer Cell 2013; 24: 695-709.
71. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 2010; 70: 5728-5739.
72. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation, polarization. Front Biosci 2008; 13: 453-461.
73. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, et al. HIF-1alpha regulates function, differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 2010; 207: 2439-2453.
74. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function, promotes tumor progression. Cancer Res 2010; 70: 7465-7475.
75. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, et al. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues, hypoxia-regulated gene therapy. Am J Pathol 2003; 163: 1233-1243.
76. Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM. Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis. Neoplasia 2001; 3: 459-468.
77. Hasmim M, Noman MZ, Messai Y, Bordereaux D, Gros G, Baud V, et al. Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells, macrophages via direct regulation of TGF-beta1. J Immunol 2013; 191: 5802-5806.
78. Cairns RA, Harris I, McCracken S, Mak TW. Cancer cell metabolism. Cold Spring Harb Symp Quant Biol 2011; 76: 299-311.
79. Bellone M, Calcinotto A. Ways to enhance lymphocyte trafficking into tumors, fitness of tumor infiltrating lymphocytes. Front Oncol 2013; 3: 231.
80. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status, future directions. Lancet 2016; e-pub ahead of print 4 February 2016; doi:10.1016/S0140-6736(15)01088-0.
81. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014; 20: 607-615.
82. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1, CTLA-4 combination blockade expands infiltrating T cells, reduces regulatory T, myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 2010; 107: 4275-4280.
83. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab, Ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23-34.
84. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. 2014. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 15: 700-712.
85. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33: 828-833.
86. Widmer DS, Hoek KS, Cheng PF, Eichhoff OM, Biedermann T, Raaijmakers MI, et al. Hypoxia contributes to melanoma heterogeneity by triggering HIF1alphadependent phenotype switching. J Invest Dermatol 2013; 133: 2436-2443.
87. Lin Q, Yun Z. Impact of the hypoxic tumor microenvironment on the regulation of cancer stem cell characteristics. Cancer Biol Ther 2010; 9: 949-956.
88. Yeung TM, Gandhi SC, Bodmer WF. Hypoxia, lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci USA 2011; 108: 4382-4387.
89. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression, metastasis. Nat Med 2013; 19: 1423-1437.
90. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015; 348: 69-74.
91. Kotsakis A, Vetsika EK, Christou S, Hatzidaki D, Vardakis N, Aggouraki D, et al. Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reverse transcriptase (TERT) peptide: results of an expanded phase II study. Ann Oncol 2012; 23: 442-449.
92. Scardino A, Gross DA, Alves P, Schultze JL, Graff-Dubois S, Faure O, et al. HER-2/neu, hTERT cryptic epitopes as novel targets for broad spectrum tumor immunotherapy. J Immunol 2002; 168: 5900-5906.
93. Saggar JK, Yu M, Tan Q, Tannock IF. The tumor microenvironment, strategies to improve drug distribution. Front Oncol 2013; 3: 154.
94. Becker JC, Andersen MH, Schrama D, Thor Straten P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 2013; 62: 1137-1148.
95. Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J. Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 2008; 38: 2412-2418.
96. Sceneay J, Parker BS, Smyth MJ, Moller A. Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology 2013; 2: e22355.
97. Krtolica A, Le Moan N, Serwer L, Yoshida Y, Ozawa T, Butowski N, et al. Treatment with OMX-4.80, a tumor-penetrating tunable oxygen carrier, reduces tumor hypoxia, dramatically enhances radiation therapy in intra-cranial models of glioblastoma. Neuro Oncol 2014; 16(Suppl 2): ii3-ii4.
98. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11: 393-410.
99. Metelo AM, Noonan H, Iliopoulos O. HIF2a inhibitors for the treatment of VHL disease. Oncotarget 2015; 6: 23036-23037.
100. Xia Y, Choi HK, Lee K. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem 2012; 49: 24-40.