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McKenna et al Hypoxia in prostate cancer

contributing factor to resistance mechanisms under to result in a number of alterations and include (1)
acute hypoxia but not chronic fractions of solid alteration of the catalytic activity of drug-metabolizing
tumors [31] . HAPs such as AQ4N that rely on an aliphatic enzymes that are responsible for HAP bioconversion,
tertiary amine N-oxide are activated via two-electron and (2) the DDR may be differently regulated in different
reduction that is catalysed by CYP isoforms [36-41] is types of cells, e.g. a hypoxic cell and a hypoxia-located
not oxygen sensitive and hence a more persistent cell cancer stem cell. Some evidence indicate that hypoxia-
killing effect may be observed; the more metabolically induced DDR under more extreme hypoxia (< 0.1%)
stable, deuterated analogue of AQ4N, OCT1002 is occurs in the absence of detectable single- or double-
described further below. strand breaks and in a background of repressed DNA
repair (Olcina & Hammond). In this regard, it could be
COMBINATION TREATMENT WITH HAPS important in the future to explore how DNA-targeted
metabolites derived from HAPs can be used to exploit
changes in DDR influenced by hypoxia.
It is clear from clinical results thus far that an
increased understanding of how HAPs are activated It is likely that the single electron-reduced HAPs
in different tumor types is required in order to develop could be sensitive to changes in DDR. HAPs such as
reliable predictors of tumor sensitivity to this type of tirapazamine and PR-104A that are reduced to DNA-
treatment. Moreover, as with most chemotherapeutic reactive metabolites via one-electron reduction have
drugs, it is unlikely that monotherapy with any given been shown to be more potent in cancer cells harbouring
HAP will prove to be wholly effective. A more realistic DDR pathways that include dysfunctional homologous
scenario is that susceptible tumors can be treated recombination repair (HRR) [46,47] . Exploitation of
with combinatorial therapy which includes a HAP. In dysfunctional HRR genes in hypoxic tumors require
the preclinical setting, enhanced anticancer activity the discovery of biomarkers that can help to predict
has been demonstrated by combining chemotherapy a better response to HAPs, however there has been
with HAPs. In prostate cancer, synergistic effect has very little systematic effort to discover and fully unravel
e.g. been achieved using doxorubicin or docetaxel the potential of such biomarkers [31] . This is in part
in combination with TH-302, supporting HAPs with due to the nature of such research, complicated by
cycle-active chemotherapy to treat aggressive forms tumor reoxygenation that often occurs as a result of
of prostate cancer [42] . spontaneous changes in blood flow and therapy with
subsequent impact on DDR pathways [48] . An example
In a clinical context, several HAPs have been of how improved understanding of the DDR machinery
investigated in combination with conventional provides an opportunity for combination therapy was
cytotoxic chemotherapy or radiotherapy [43,44] . Although demonstrated by Lindquist et al. [49] who investigated the
some patients have benefitted from the combination potential for inhibiting DNA double strand break repair
therapy, the results of these trials have at large been in hypoxic cells by targeting DNA-dependent protein
disappointing as reflected upon by Hunter et al. [31] . kinase (DNA-PK). BCCA621C, a DNA-PK inhibitor was
However, with the increasing knowledge we have shown to be able to radiosensitize NCI-H460 cells under
gained, especially over the past decade, perhaps hypoxic but not normoxic conditions using a range of
other combination drugs that address molecular clinically relevant ionising radiation doses. There is also
targets, oncogenic drivers and exploit DNA damage evidence that Chk1, ATM, ATR and poly (ADP-ribose)
response (DDR) pathways will pave the way for the polymerase (PARP) are affected by hypoxia [48] . In
next generation of HAPs. regard to the latter, several PARP inhibitors are under
clinical evaluation and information from these trials will
For example, there is evidence to suggest that DDR provide key information on how HAPs could be used in
induced by hypoxia is altered from the classical combination with PARP inhibition (PARPi) alone or with
pathways induced by damaging agents [45] . There additional radiotherapy. Preclinical data have shown
are possibly several reasons for this and include that PARPi can be used as a radiosensitizing agent,
repression of DNA repair in hypoxic conditions. which may increase the efficacy of radiotherapy in
Treatment is complicated further by several reports prostate cancer [50] . Recently, Hammond and co-workers
indicating that DNA repair under hypoxia is defective have shown that olaparib and radiotherapy combination
or abnormal and hence may not respond to exposure therapy had significant effect in hypoxic lung cancer
of the bioreduced metabolites of the HAPs that have xenografts but limited efficacy in less hypoxic tumors [51] .
undergone clinical evaluation. It is possible this effect was due to hypoxia-induced
contextual synthetic cell-killing events [52] . The nature of
The complex nature of a heterogenous tumor is likely the tumor microenvironment has an impact on treatment

Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ March 1, 2018 5