Current challenges and opportunities in treating hypoxic prostate tumors

Hypoxia is a well-established characteristic of prostate tumors and is now recognised as a major contributory factor to both tumor progression and increased resistance to therapy.One strategy to target hypoxic tumor cells is the development of hypoxia-activated prodrugs(HAPs),which are activated in low oxygen environments.Several HAPs have been developed but despite encouraging results from preclinical studies many of these have performed 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 identify patients who will benefit from HAP treatment,either alone or in combination with other drugs.This review discusses the primary limitations of using HAPs to treat hypoxic tumors and explains how these challenges can be addressed.In particular,it emphasises the importance of tumor imaging and identification of reliable biomarkers for measuring hypoxia and monitoring cellular response to treatment in individual patients.Developing predictive assays for clinical use will be paramount in demonstrating the patient impact and effectiveness of HAPs for personalised medicine.

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Androgens play an important role in prostate cancer(PCa)development and progression.Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer,patients eventually relapse with the lethal form of the disease.The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor(AR).Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone(T)and dihydrotestosterone(DHT)seems to be an attractive strategy for PCa therapies.Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels,and thereby influencing PCa progression.This supports the idea for the development of multi-targeting strategies,involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis.In this review,we will focus on CYP17A1,AKR1C3,HSD17B3 and SRD5A,as these enzymes play essential roles in all the three androgenic pathways.We will review also the AR as an additional target for the design of bifunctional drugs.Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

Expression and regulation of aldehyde dehydrogenases in prostate cancer

The functional role of aldehyde dehydrogenases(ALDHs)in prostate cancer remains an area of some controversy.Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties,while evidence is also emerging about the involvement of specific isoforms in migration,invasiveness and metastasis.Identification of specific ALDH isoforms,which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer.The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention.

Introduction of the special issue “How does the prostate cancer microenvironment affect the metastatic process and/or treatment outcome?”

It is with great pleasure that we introduce this special issue titled“How does the prostate cancer microenvironment affect the metastatic process and/or treatment outcome?”.Within this issue we,and our fellow authors,explore the role of the prostate cancer microenvironment in tumour metastasis and treatment outcome.Global statistics reveal that prostate cancer is the second most common form of cancer and is attributable to fifth of all cancer-related deaths to affect men worldwide.Whilst rates of disease incidence appear to be increasing a high proportion of men diagnosed with disease will survive for ten or more years.