Current challenges and opportunities in treating hypoxic prostate tumors

Abstract

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.

Expression and regulation of aldehyde dehydrogenases in prostate cancer

“…Unravelling the PCa microenvironment is likely to offer new insight and opportunities to molecularly stratify patients for treatment, based on their tumours' hypoxic signature, including analysis of enzymes with oxidase and/ or reductase functionality. Prostate tumours are considerably hypoxic as discussed in this thematic issue [216] and enzymes such as ALDHs are likely to be expressed differentially within the TME due to different pressures including hypoxic stress and types of cells such as MDR and CSCs.…”

miR‐210 is induced by hypoxia and regulates neural cell adhesion molecule in prostate cells

“…This is an important factor in cancer progression because hypoxic stress triggers a complex network of cellular and molecular responses that can promote tumour growth (Araos, Sleeman, & Garvalov, 2018; Muz et al, 2015). This is particularly significant for prostate tumours which are known to be very hypoxic in comparison to normal prostate tissue (McKeown et al, 2014; McKenna, Errington, & Pors, 2018). Prostate tumour hypoxia has been implicated as a contributory factor in malignant progression (Rudolfsson & Bergh, 2009; Tsai & Wu, 2012), genetic instability (Taiakina, Pra, & Bristow, 2014), epithelial‐to‐mesenchymal transition (EMT; Byrne et al, 2016; Li et al, 2016) and the selection of cells with diminished apoptotic potential and a greater invasive potential (Butterworth et al, 2008; Graeber et al, 1996).…”

Hypoxia in prostate cancer

“…Dear Editor, I have read with great interest the review "Current challenges and opportunities in treating hypoxic prostate tumors" by McKenna et al [1] . In this review, the authors present, as a key information in Table 1 In their article, McKenna et al [1] have reviewed current knowledge about the impact of the "hallmark feature" hypoxia on pathways promoting cancer growth, malignant progression, therapeutic resistance and tumor immune escape [5][6][7] .…”

“…In this review, the authors present, as a key information in Table 1 In their article, McKenna et al [1] have reviewed current knowledge about the impact of the "hallmark feature" hypoxia on pathways promoting cancer growth, malignant progression, therapeutic resistance and tumor immune escape [5][6][7] . Certainly, this information is of utmost interest to experimental and clinical oncologists.…”