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McKenna et al Hypoxia in prostate cancer

is likely to reside in the vast arrays of data detailing stratify patients for treatment, which possibly could
the specific genetic characteristics of individual include hypoxia targeting in selected groups. As data
prostate tumors which has been gathered by on clinical samples and patient outcome continues
genomic profiling in recent years. Comprehensive to be collected and archived in data repositories like
bioinformatics analyses of this data has revealed that The Cancer Genome Atlas, these genetic signatures
a wide molecular diversity exists in human cancer, can be continually refined by bioinformatic analysis to
including prostate tumors (TCGA Network, 2015) identify the most reliable markers of prostate tumor
[73] . Such tumor heterogeneity may help explain why hypoxia.
patients presenting with pathologically similar tumors
can have very different responses to the same course In addition to tumor analysis, non-invasive biomarkers
of treatment. For example, primary prostate cancers which can be measured in biofluids are also an
exhibit a wide variability in AR activity, with increased attractive option for clinical use. In this regard,
AR-dependent signalling linked to gene mutations in microRNAs have generated much excitement as
SPOP and FOXA1 (TCGA Network, 2015) [73] . Knowing potentially valuable markers of prostate progression
whether a tumor carries these mutations or not can and treatment response. These small RNA molecules
help determine the most appropriate ADT approach are much more stably preserved than other RNA
for a patient and subsequent tracking of those gene species in clinical samples, including fresh and fixed
mutations can inform adaptive drug administration. tissues, serum and urine, and can be readily detected
Likewise, knowing the mutational status of the AR using highly specific and sensitive PCR-based assays.
gene itself will be critical in helping predict treatment miRNAs are important regulators of cell function and
outcome. For instance, enzalutamide cannot bind to many of them are aberrantly expressed in prostate
an abnormal splice variant of the AR called AR-V7, so cancer [80,81] . Of these, miR-210 has been identified as a
patients harbouring this mutation would be unlikely to key regulator of hypoxia [82,83] and has been implicated
respond to that particular drug, further emphasising in prostate cancer progression [84] . Significantly, serum
the need to stratify patients by molecular profiles. levels of miR-210 have been shown to be elevated in
Indeed, recent research has shown that AR-V7 can prostate cancer patients compared to benign prostatic
be detected in patient blood samples and efforts to hyperplasia controls [85] , as well as in metastatic CRPC
validate this screening for clinical application are patients who did not respond to treatment [86] . The goal
under way [74] . is that miR-210 and other related miRNAs can be used
as a panel of serum biomarkers that will reflect extent
In a similar manner, it is possible to probe this data of tumor hypoxia.
for hypoxic markers, allowing researchers to identify
key patterns which may allow patient stratification It is therefore clear that any strategies for treating
based on hypoxic indices. Hypoxic gene signatures prostate cancer must embrace molecular profiling as
with prognostic potential have been identified in a means to stratify patients and also monitor response
various cancers, such as breast [75] , head and neck [76] to treatment. Since hypoxia plays such a fundamental
and laryngeal cancer [77] , each study highlighting role in prostate cancer progression, examining the
how expression of genes related to hypoxia can altered expression of genes involved in hypoxia-
be used to predict outcome. In a prostate cancer related pathways, as well as network analysis of their
setting, a combination of these signatures was interactions, will be an important consideration in
subsequently used to categorise hypoxic status of a developing precision medicine for individual patients.
total of 271 radical prostatectomy samples from two
independent cohorts in a study which showed that CONCLUSION
biochemical relapse was associated with indices
of tumor hypoxia, genomic instability, and genomic A major challenge in cancer therapy is to develop
subtypes based on multivariate analyses [78] . Patients therapeutic agents that selectively target tumor
with a low percentage of genome alteration and low cells. One avenue towards the development of more
hypoxia had the best outcome, whereas those with selective cancer therapies is to exploit the unique
high levels of both measures had the worst. Another physiological properties of solid tumors using prodrug
study investigated gene expression in prostate approaches. Hypoxia generated as a result of a poor
tumor biopsies staining positive for hypoxia marker and inefficient neovasculature is a characteristic
pimonidazole and also identified a signature of feature of many solid tumors and is associated with
hypoxic response genes which correlated with tumor the development of an aggressive phenotype and
aggressiveness [79] . These studies demonstrate the resistance to radiotherapy and chemotherapy. Whilst
value of genetic profiling of hypoxic status to help problematical for conventional therapies, hypoxia is

8 Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ March 1, 2018