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McKenna et al Hypoxia in prostate cancer

outcome. Veliparib has been shown to potentiate PC-3 previous studies in the same model which showed
but not DU-145 tumors to radiotherapy, which may be that bicalutamide induces hypoxia through vascular
correlated with higher levels of hypoxia in PC-3 tumors collapse [15,57] resulting in molecular changes that
compared with DU-145 tumors [53] . These studies did not included evidence of endothelial to mesenchymal
include pharmacokinetics of either olaparib or veliparib transition and increased metastasis to the lungs
and hence the distribution of the PARP inhibitors within within 4 weeks [15] . These hypoxia-induced responses
the tumor microenvironment is unknown. It is tempting to may help explain why patients treated solely with
speculate that improved delivery of the PARP inhibitors ADT often relapse; the hypoxic stress selects for
to the hypoxic fractions or inclusion of an appropriate resistant cells which survive to establish a tumor
HAP could lead to an enhanced therapeutic index. with a more malignant phenotype. Along with other
studies investigating the link between hypoxia ADT on
USE OF OCT1002 TO IMPROVE EXISTING tumors [59,60] , this lends weight to the idea that drug-
induced hypoxia may in fact drive prostate cancer
THERAPY progression and that HAPs may be a valuable way to
address this issue.
Research in our own labs have focused on how uHAPs
can improve androgen deprivation therapy (ADT) for This is timely work as the idea of combinatorial
prostate tumors. Most HAPs are reduced in single- drug treatment has gained considerable traction in
electron reduction steps, a process which is reversible recent years. In particular, recent results from the
if oxygen levels increase. However, AQ4N [54] , its CHAARTED [61] and STAMPEDE [62] clinical trials
deuterated analogue OCT1002 (OncoTherics Ltd) [55] have revealed that use of docetaxel in combination
and AQ4N analogues with potential to covalently with ADT improved relapse-free survival in patients
adduct DNA/topo II [56] can be considered uHAPs. with high-risk localised prostate cancer, proving that
These compounds are alkylaminoanthraquinone di- combining ADT with other types of drug can benefit
N-oxides, which are irreversibly bioactivated via a prostate cancer sufferers. Since hypoxia is a major
two-step, two electron reduction to form the reduction factor in developing ADT resistance, it makes sense
products (AQ4 and OCT1001, respectively). These to combine ADT with HAPs or uHAPs as a therapeutic
are metabolically stable, highly toxic DNA-affinic strategy. However, as discussed above the absolute
reduction products which exist independent of any requirement for patient derived evidence-led decision
further change in oxygenation. OCT1002 differs making during clinical development of various HAPs
from AQ4N through highly selective deuterium demonstrates that translating these compounds into
substitution of the 12 hydrogen atoms contained clinically accepted drugs needs careful consideration
within the two N-oxide side chains [55] . This results of tumor micro-environment and related hypoxic
in superior intracellular persistence of the activated status. It requires both improved understanding of
form OCT1001, since deuteration slows cytochrome the action of these agents, as well as methods with
P450 metabolism, alters subcellular localisation and which to clearly identify tumors which will be sensitive
sequestration properties, thereby contributing to an to HAPs. We still need improved ways to predict
enhanced intracellular persistence of the activated which patients will respond to which drugs. Making
drug as described for other drugs [57,58] . Consequently, the right decisions on whether to use HAPs require
it is predicted that OCT1002 should be an improved increased knowledge about the hypoxic mechanisms
analogue and is therefore under extensive preclinical which drive prostate cancer progression in order to
evaluation. improve patient stratification in the clinic. This means
developing accurate, sensitive ways to identify tumors
A recent study has investigated how OCT1002 may that are likely to be susceptible to hypoxic targeting.
be combined with existing therapies for prostate
cancer to prevent ADT resistance and progression to DETECTION OF PRODRUG CONVERSION
castrate resistant prostate cancer (CRPC) [55] . It was AND PREDICTION OF RESPONSES TO HAPS
shown that OCT1002 has a hypoxia-dependent anti-
tumor effect in androgen-sensitive LNCaP prostate The key to ascertaining or indeed stratifying a prostate
tumor xenografts and the effect can be markedly tumor for sensitivity to hypoxia targeting through
enhanced when combined with bicalutamide, an ADT HAP treatment requires a multi-pronged approach
drug which inhibits androgen signaling by targeting which has to take into consideration multiple aspects.
the androgen receptor (AR). The study also showed Importantly this requirement provides an opportunity
that it could block significantly the molecular changes to bring new technologies and innovations to bear
caused by bicalutamide alone. This is consistent with in order to really elucidate the effectiveness of the
6 Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ March 1, 2018