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McKenna et al. J Cancer Metastasis Treat 2018;4:1-13 Journal of
DOI: 10.20517/2394-4722.2017.54
Cancer Metastasis and Treatment

www.jcmtjournal.com
Topic: How does the prostate cancer microenvironment affect the metastatic Open Access
process and/or treatment outcome?

Current challenges and opportunities in
treating hypoxic prostate tumors

Declan J. McKenna , Rachel Errington , Klaus Pors 3
2
1
1 Biomedical Sciences Research Institute, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
2 School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
3 Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, West Yorkshire, UK.
Correspondence to: Dr. Declan J. McKenna, Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine BT52 1SA,
Northern Ireland, UK. E-mail: dj.mckenna@ulster.ac.uk

How to cite this article: McKenna DJ, Errington R, Pors K. Current challenges and opportunities in treating hypoxic prostate tumors. J Cancer
Metastasis Treat 2018;4:1-13.

ABSTRACT
Article history: Hypoxia is a well-established characteristic of prostate tumors and is now recognised as
Received: 31 Oct 2017 a major contributory factor to both tumor progression and increased resistance to therapy.
First Decision: 4 Dec 2017 One strategy to target hypoxic tumor cells is the development of hypoxia-activated prodrugs
Revised: 25 Dec 2017 (HAPs), which are activated in low oxygen environments. Several HAPs have been developed
Accepted: 25 Dec 2017 but despite encouraging results from preclinical studies many of these have performed
Published: 1 Mar 2018 disappointingly in clinical trials. In the developing era of precision medicine, it is clear that
more strategic deployment of these agents is required, based on reliable methods that can
Key words: identify patients who will benefit from HAP treatment, either alone or in combination with
Hypoxia, other drugs. This review discusses the primary limitations of using HAPs to treat hypoxic
prostate cancer, tumors and explains how these challenges can be addressed. In particular, it emphasises
hypoxia activated prodrugs, the importance of tumor imaging and identification of reliable biomarkers for measuring
OCT1002, hypoxia and monitoring cellular response to treatment in individual patients. Developing
AQ4N, predictive assays for clinical use will be paramount in demonstrating the patient impact and
bioinformatics, effectiveness of HAPs for personalised medicine.
DNA damage,
combination therapies

INTRODUCTION which are primarily mediated through hypoxia-inducible
[4]
factors (HIFs) . When cellular oxygen levels are
normal HIFα subunits are degraded by the proteasome
A large body of evidence now exists to show that following hydroxylation by prolyl hydroxylase domain
hypoxia occurs in most solid tumors and can have (PHD) proteins and poly-ubiquination by the von
a major influence on treatment response [1-3] . Under Hippel-Lindau tumor suppressor, which is the substrate
hypoxic stress, cells respond in a number of ways recognition component of an E3-ubiquitin ligase. When

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