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McKenna et al Hypoxia in prostate cancer

regarded as a valid target for drug development and a (New compounds and uses thereof [CA2881324A1])
series HAPs have been developed over a period of 30- and non-executive director of Biostatus Ltd which is the
40 years with eight HAPs reaching clinical evaluation. current assignee. Rachel Errington is a shareholder of
Currently, no HAP has reached the market and this Oncotherics Ltd.
is somewhat perplexing given the overwhelming
evidence of solid tumors containing significant Patient consent
levels of acute and chronic hypoxia. If patients Not applicable.
were molecularly stratified for treatment based on
their tumor hypoxia signature including analysis of Ethics approval
reductase expression, it is possible that the HAPs Not applicable.
in combination with chemotherapy or radiotherapy
would have resulted in improved treatment outcomes. Copyright
Prostate tumors are considerably hypoxic as discussed © The Author(s) 2018.
in this review, which poses some unique challenges to
effective treatment of aggressive forms of this disease REFERENCES
with standard therapies such as docetaxel and/or
radiotherapy. Clinical trials carried out with AQ4N have 1. Moeller BJ, Richardson RA, Dewhirst MW. Hypoxia and
been promising, demonstrating safe administration of radiotherapy: opportunities for improved outcomes in cancer
a uHAP that rapidly distributes throughout the body treatment. Cancer Metastasis Rev 2007;26:241-8.
and penetrates into hypoxic regions where it is bio- 2. Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel
reduced to a persistent DNA-affinic topo II-targeting insights on the functional interaction of HIFs and cell death
metabolite. The deuterated AQ4N analogue OCT1002 pathways. Drug Resist Updat 2011;14:191-201.
offers great potential in the treatment of prostate 3. McKeown SR. Defining normoxia, physoxia and hypoxia in tumours-
cancer, for example in the combination with ADT. 4. implications for treatment response. Br J Radiol 2014;87:20130676.
Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation,
In prostate cancer, uHAPs could also be used in and cancer. Int J Cancer 2016;138:1058-66.
combination with PARP1 inhibitors in patients whose 5. Bruick RK, McKnight SL. A conserved family of prolyl-4-
tumors harbour DDR deficiencies. Much progress is hydroxylases that modify HIF. Science 2001;294:1337-40.
being made on how best to utilise PARP1 inhibitors 6. Tarrado-Castellarnau M, de Atauri P, Cascante M. Oncogenic
but prior analysis of tumor heterogeneity and target regulation of tumor metabolic reprogramming. Oncotarget
expression is vital for clinical success. For example, 2016;7:62726-53.
a recent phase 2 trial that concerned patients with 7. Luo F, Shi J, Shi Q, Xu X, Xia Y, He X. Mitogen-activated protein
metastatic prostate cancer benefitted from whole- kinases and hypoxic/ischemic nephropathy. Cell Physiol Biochem
exome sequencing and transcriptome analysis on 2016;39:1051-67.
DNA from fresh-frozen tumor-biopsy samples prior to 8. D’Ignazio L, Bandarra D, Rocha S. NF-kappaB and HIF crosstalk in
immune responses. FEBS J 2016;283:413-24.
treatment. In this study, understanding of DNA defects 9. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in
enabled clinicians to select patients suitable for the cancer progression, angiogenesis, metastasis, and resistance to
PARP inhibitor olaparib to ensure better treatment therapy. Hypoxia (Auckl) 2015;3:83-92.
outcome [87] . Finally, the emergence of genetic and 10. Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science
hypoxic signatures and the ability to image and 2016;352:175-80.
analyse the heterogeneity of prostate tumors provides 11. Vaupel P, Hockel M, Mayer A. Detection and characterization
new opportunities for employing HAPs and uHAPs in of tumor hypoxia using pO2 histography. Antioxid Redox Signal
combination with molecularly-targeted agents and/or 2007;9:1221-35.
radiotherapy. 12. Rudolfsson SH, Bergh A. Hypoxia drives prostate tumour progression
and impairs the effectiveness of therapy, but can also promote cell
death and serve as a therapeutic target. Expert Opin Ther Targets
DECLARATIONS 2009;13:219-25.
13. Tsai YP, Wu KJ. Hypoxia-regulated target genes implicated in tumor
Authors’ contributions metastasis. J Biomed Sci 2012;19:102.
The authors contributed equally to the manuscript 14. Taiakina D, Dal Pra A, Bristow RG. Intratumoral hypoxia as the
writing and editing. genesis of genetic instability and clinical prognosis in prostate cancer.
Adv Exp Med Biol 2014;772:189-204.
Financial support and sponsorship 15. Byrne NM, Nesbitt H, Ming L, McKeown SR, Worthington J,
McKenna DJ. Androgen deprivation in LNCaP prostate tumour
None. xenografts induces vascular changes and hypoxic stress, resulting
in promotion of epithelial-to-mesenchymal transition. Br J Cancer
Conflicts of interest 2016;114:659-68.
Professor Rachel Errington is a co-inventor of OCT 1002 16. Li MC, Wang YX, Luo Y, Zhao JH, Li Q, Zhang J, Jiang

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