Targeting HIF-1 for prostate cancer: a synthesis of preclinical evidence

ABSTRACT

Introduction

Hypoxia-inducible factor (HIF) mediates multiple intracellular processes that drive cellular metabolism and induce proliferation. Dysregulated HIF expression is associated with oncogenic cellular transformation. Moreover, high HIF levels correlate with tumor aggressiveness and chemoresistance, indicating the vital effect of HIF-1α on tumorigenicity. Currently, widespread in-vitro and in-vivo research is focusing on targeting HIF with drugs that have already been approved for use by the FDA, such as belzutifan, in renal cell carcinoma. HIF inhibition is mostly associated with tumor size reduction; however, drug toxicity remains a challenge.

Area covered

In this review, we focus on the potential of targeting HIF in prostate cancer (PC) and summarize the scientific background of HIF activity in PC. This finding emphasizes the rationale for using HIF as a therapeutic target in this malignancy. We have listed known HIF inhibitors that are being investigated in preclinical studies and their potential as anticancer drugs for PC.

Expert opinion

Although HIF-targeting agents have been investigated for over a decade, their use in therapy-resistant cancers remains relevant and should be explored further. In addition, the use of naturally occurring HIF inhibitors should be considered as an add-on therapy for the currently used regimens.

KEYWORDS:

• Androgen receptor
• hypoxia-inducible factor
• HIF
• preclinical studies
• prostate adenocarcinoma
• castration-resistant
• prostate cancer

Article highlights

• Hypoxia has a major role in tumor survival and proliferation.

• HIF-1α dysregulation in neoplastic processes contributes to tumor aggressiveness and chemoresistance

• HIF operates parallelly in multiple pathways, which altogether take part in prostate cancer development

• High HIF-1α levels are associated with aggressive prostate cancer

• Targeting HIF-1α in preclinical studies using prostate cancer cells models showed an effective anti-proliferative pro-apoptotic activity

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose

Acknowledgments

To Drs Bezalel Sivan and Ben Hefer for their help in preparation of the manuscript.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2023.2248381.

Additional information

Funding

This paper was not funded.