HIF Inhibitors: Status of Current Clinical Development
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.
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.
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.
KeywordsHIF HIF inhibitor Hypoxia inducible factor Renal cell carcinoma VEGF VHL
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 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.Google Scholar
- 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.Google Scholar
- 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.Google Scholar
- 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.Google Scholar
- 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. PubMedGoogle Scholar
- 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. PubMedGoogle Scholar
- 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. PubMedGoogle Scholar
- 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.PubMedPubMedCentralGoogle Scholar