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HIF Inhibitors: Status of Current Clinical Development

Abstract

Purpose of Review

In this review, the importance of the hypoxia inducible factor (HIF) pathway in tumorigenesis and cancer treatment outcomes will be discussed. The outcomes of phase II and III clinical trials of direct HIF inhibitors in the treatment of cancer will be reviewed.

Recent Findings

The HIF signaling pathway is activated by tumor-induced hypoxia or by inactivating mutations of the VHL gene. HIF is a transcription factor which regulates the expression of genes involved in adjusting mechanisms to hypoxia such as angiogenesis or apoptosis as well as tumor growth, invasion, and metastasis. The HIF pathway has a key role in development of resistance to different treatment modalities and higher expression of the HIF molecule is associated with poor prognosis.

Summary

Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies of the HIF inhibitors either as a single agent or in combination with other therapeutic agents.

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References

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

  1. 1.

    Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci U S A. 1991;88(13):5680–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Luo JC, Shibuya M. A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1alpha, 2alpha and 3alpha). Oncogene. 2001;20(12):1435–44.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. 2007;2007(407):cm8.

    PubMed  Article  Google Scholar 

  5. 5.

    Krieg M, Haas R, Brauch H, Acker T, Flamme I, Plate KH. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene. 2000;19(48):5435–43.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood. 2005;105(2):659–69.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269(38):23757–63.

    CAS  PubMed  Google Scholar 

  8. 8.

    Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci. 2012;37(9):364–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207(11):2439–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Chiu DK, Tse AP, Xu IM, Di Cui J, Lai RK, Li LL, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun. 2017;8(1):517.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Bollinger T, Gies S, Naujoks J, Feldhoff L, Bollinger A, Solbach W, et al. HIF-1alpha- and hypoxia-dependent immune responses in human CD4+CD25high T cells and T helper 17 cells. J Leukoc Biol. 2014;96(2):305–12.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    He LY, Li L, Guo ML, Zhang Y, Zhang HZ. Relationship between CD4+CD25+ Treg and expression of HIF-1alpha and Ki-67 in NSCLC patients. Eur Rev Med Pharmacol Sci. 2015;19(8):1351–5.

    PubMed  Google Scholar 

  14. 14.

    Kaidi A, Qualtrough D, Williams AC, Paraskeva C. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 2006;66(13):6683–91.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Choudhry H, Albukhari A, Morotti M, Haider S, Moralli D, Smythies J, et al. Tumor hypoxia induces nuclear paraspeckle formation through HIF-2alpha dependent transcriptional activation of NEAT1 leading to cancer cell survival. Oncogene. 2015;34(34):4482–90.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Yoo YG, Christensen J, Huang LE. HIF-1alpha confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function. Cancer Res. 2011;71(4):1244–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Yang J, Zhang X, Zhang Y, Zhu D, Zhang L, Li Y, et al. HIF-2alpha promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J Exp Clin Cancer Res. 2016;35:26.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Wu H, Huang S, Chen Z, Liu W, Zhou X, Zhang D. Hypoxia-induced autophagy contributes to the invasion of salivary adenoid cystic carcinoma through the HIF-1alpha/BNIP3 signaling pathway. Mol Med Rep. 2015;12(5):6467–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Zhang Y, Yan J, Wang L, Dai H, Li N, Hu W, et al. HIF-1alpha promotes breast cancer cell MCF-7 proliferation and invasion through regulating miR-210. Cancer Biother Radiopharm. 2017;32(8):297–301.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Sun Y, Guan Z, Liang L, Cheng Y, Zhou J, Li J, et al. HIF-1alpha/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer. Oncol Rep. 2016;35(3):1549–56.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Sowa T, Menju T, Chen-Yoshikawa TF, Takahashi K, Nishikawa S, Nakanishi T, et al. Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression. Cancer Med. 2017;6(1):288–97.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F, et al. Inhibition of HIF-1alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget. 2015;6(4):2250–62.

    PubMed  Article  Google Scholar 

  23. 23.

    Gao ZJ, Yuan WD, Yuan JQ, Yuan K, Wang Y. Downregulation of HIF-2alpha reverse the chemotherapy resistance of lung adenocarcinoma A549 cells to cisplatin. Med Sci Monit. 2018;24:1104–11.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  24. 24.

    Semenza GL. Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell. 2004;5(5):405–6.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Schwartz DL, Bankson J, Bidaut L, He Y, Williams R, Lemos R, et al. HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance. Mol Cancer Res. 2011;9(3):259–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Pore N, Gupta AK, Cerniglia GJ, Jiang Z, Bernhard EJ, Evans SM, et al. Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res. 2006;66(18):9252–9.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Okuno T, Kawai K, Hata K, Murono K, Emoto S, Kaneko M, et al. SN-38 acts as a radiosensitizer for colorectal cancer by inhibiting the radiation-induced up-regulation of HIF-1alpha. Anticancer Res. 2018;38(6):3323–31.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    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 and invasion. Cancer Cell. 2008;13(3):206–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Opdenakker G, Van den Steen PE, Van Damme J. Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol. 2001;22(10):571–9.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, et al. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 2001;61(17):6548–54.

    CAS  PubMed  Google Scholar 

  31. 31.

    Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012;30(32):4026–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Lai XM, Liu SY, Tsai YT, Sun GH, Chang SY, Huang SM, et al. HAF mediates the evasive resistance of anti-angiogenesis TKI through disrupting HIF-1alpha and HIF-2alpha balance in renal cell carcinoma. Oncotarget. 2017;8(30):49713–24.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Zhao D, Zhai B, He C, Tan G, Jiang X, Pan S, et al. Upregulation of HIF-2alpha induced by sorafenib contributes to the resistance by activating the TGF-alpha/EGFR pathway in hepatocellular carcinoma cells. Cell Signal. 2014;26(5):1030–9.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z, Du X, et al. A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76(18):5491–500.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    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(2):396–403.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    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(4):623–32.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Dai X, Pi G, Yang SL, Chen GG, Liu LP, Dong HH. Association of PD-L1 and HIF-1alpha coexpression with poor prognosis in hepatocellular carcinoma. Transl Oncol. 2018;11(2):559–66.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Lim E, Kuo CC, Tu HF, Yang CC. The prognosis outcome of oral squamous cell carcinoma using HIF-2alpha. J Chin Med Assoc. 2017;80(10):651–6.

    PubMed  Article  Google Scholar 

  40. 40.

    Gao ZJ, Wang Y, Yuan WD, Yuan JQ, Yuan K. HIF-2alpha not HIF-1alpha overexpression confers poor prognosis in non-small cell lung cancer. Tumour Biol. 2017;39(6):1010428317709637.

    PubMed  Google Scholar 

  41. 41.

    Zheng Y, Ni Y, Huang X, Wang Z, Han W. Overexpression of HIF-1alpha indicates a poor prognosis in tongue carcinoma and may be associated with tumour metastasis. Oncol Lett. 2013;5(4):1285–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Sun W, Shen ZY, Zhang H, Fan YZ, Zhang WZ, Zhang JT, et al. Overexpression of HIF-1alpha in primary gallbladder carcinoma and its relation to vasculogenic mimicry and unfavourable prognosis. Oncol Rep. 2012;27(6):1990–2002.

    CAS  PubMed  Google Scholar 

  43. 43.

    Wang Q, Hu DF, Rui Y, Jiang AB, Liu ZL, Huang LN. Prognosis value of HIF-1alpha expression in patients with non-small cell lung cancer. Gene. 2014;541(2):69–74.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Lodewijk L, van Diest P, van der Groep P, Ter Hoeve N, Schepers A, Morreau J, et al. Expression of HIF-1alpha in medullary thyroid cancer identifies a subgroup with poor prognosis. Oncotarget. 2017;8(17):28650–9.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. 2016;164:152–69.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Harrison MR, Hahn NM, Pili R, Oh WK, Hammers H, Sweeney C, et al. A phase II study of 2-methoxyestradiol (2ME2) NanoCrystal(R) dispersion (NCD) in patients with taxane-refractory, metastatic castrate-resistant prostate cancer (CRPC). Investig New Drugs. 2011;29(6):1465–74.

    CAS  Article  Google Scholar 

  47. 47.

    Rajkumar SV, Richardson PG, Lacy MQ, Dispenzieri A, Greipp PR, Witzig TE, et al. Novel therapy with 2-methoxyestradiol for the treatment of relapsed and plateau phase multiple myeloma. Clin Cancer Res. 2007;13(20):6162–7.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Bruce JY, Eickhoff J, Pili R, Logan T, Carducci M, Arnott J, et al. A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate. Investig New Drugs. 2012;30(2):794–802.

    CAS  Article  Google Scholar 

  49. 49.

    Matei D, Schilder J, Sutton G, Perkins S, Breen T, Quon C, et al. Activity of 2 methoxyestradiol (Panzem NCD) in advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis: a Hoosier oncology group trial. Gynecol Oncol. 2009;115(1):90–6.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Kulke MH, Chan JA, Meyerhardt JA, Zhu AX, Abrams TA, Blaszkowsky LS, et al. A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol. 2011;68(2):293–300.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Ronnen EA, Kondagunta GV, Ishill N, Sweeney SM, Deluca JK, Schwartz L, et al. A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma. Investig New Drugs. 2006;24(6):543–6.

    CAS  Article  Google Scholar 

  52. 52.

    Oki Y, Copeland A, Romaguera J, Fayad L, Fanale M, Faria Sde C, et al. Clinical experience with the heat shock protein-90 inhibitor, tanespimycin, in patients with relapsed lymphoma. Leuk Lymphoma. 2012;53(5):990–2.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Heath EI, Hillman DW, Vaishampayan U, Sheng S, Sarkar F, Harper F, et al. A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin Cancer Res. 2008;14(23):7940–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol. 2009;27(12):2052–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Haas NB, Quirt I, Hotte S, McWhirter E, Polintan R, Litwin S, et al. Phase II trial of vorinostat in advanced melanoma. Investig New Drugs. 2014;32(3):526–34.

    CAS  Article  Google Scholar 

  56. 56.

    • Mann BS, Johnson JR, He K, Sridhara R, Abraham S, Booth BP, et al. Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin Cancer Res. 2007;13(8):2318–22 Vorinostat was recently approved by FDA for treatment of patients with cutaneous T-cell lymphoma, based on results of a phase II single arm clinical trial.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Ogura M, Ando K, Suzuki T, Ishizawa K, Oh SY, Itoh K, et al. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Br J Haematol. 2014;165(6):768–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    • Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, et al. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015;16(4):447–56 A double-blinded randomized phase III trial in patients with advanced malignant pleural mesothelioma who received vorinostat or placebo and there was no statistically significant difference in median overall survival of treatment arms.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    • 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-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36(9):867–74 Safety and efficacy of first-in-class HIF-2 inhibitor PT2385 was assessed in this phase I/II clinical trial of patients with metastatic RCC. PT2385 was well tolerated and 66% of patients had clinical benefit with treatment.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Garrett CR, Bekaii-Saab TS, Ryan T, Fisher GA, Clive S, Kavan P, et al. Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer. 2013;119(24):4223–30.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    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(8):1579–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23(17):3923–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Correspondence to Brian I. Rini.

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Fallah, J., Rini, B.I. HIF Inhibitors: Status of Current Clinical Development. Curr Oncol Rep 21, 6 (2019). https://doi.org/10.1007/s11912-019-0752-z

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Keywords

  • HIF
  • HIF inhibitor
  • Hypoxia inducible factor
  • Renal cell carcinoma
  • VEGF
  • VHL