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Page 782 Fabbrizi et al. Cancer Drug Resist 2020;3:775-90 I http://dx.doi.org/10.20517/cdr.2020.49

Hypoxia
Hypoxia is well known to contribute to poor prognosis and treatment resistance in HNSCC, therefore
hypoxic modulation has been investigated particularly in a clinical setting in order to restore sensitivity
to treatment. However, oxygenation treatments are not routinely used clinically because there is no
ideal technique to quantify tumor hypoxia and no effective treatment to modify hypoxic conditions.
Many hypoxia targeting methodologies have been proposed and tested, including hyperbaric oxygen,
[87]
hyperthermia, and agents targeting tumor blood flow . Currently, oxygen-mimetic radiosensitisers, such
as the nitroimidazoles, are the most promising compounds for overcoming hypoxia. Whilst etanidazole
[88]
failed to show benefit in advanced HNSCC patients in combination with RT in a phase III clinical trial ,
nimorazole has been demonstrated clinically to be an effective radiosensitiser for HPV-negative but not for
HPV-positive HNSCC [89-91] . Following these investigations and further results of studies from the Danish
Head and Neck Cancer Group, nimorazole has become standard of care to HNSCC patients in combination
with RT in Denmark. A phase III trial examining nimorazole efficacy with RT in locally advanced HNSCC
is currently ongoing in the UK . Recently, a group of novel nitroimidazole alkylsulfonamides have been
[92]
tested using a prodrug approach in order to increase solubility and improve drug delivery, with some of
them at least showing promising results in their ability to radiosensitise anoxic colorectal cancer cells
[93]
in vitro .
Several other agents have been investigated for overcoming tumor hypoxia, including those targeting tumor
blood flow and drugs targeting hypoxia-induced proteins. Vascular disrupting agents (VDAs) alter tumor
blood flow by increasing vascular permeability through tubulin binding on endothelial cells, whilst possibly
activating apoptosis . 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a flavone acetic acid analogue
[94]
that showed promising results as a monotherapy in reducing growth of HPV-negative HNSCC xenografts
[95]
in mice . DMXAA may also interact with tumour necrosis factor, leading ultimately to tumor oxygenation
[96]
and increased radiosensitivity . However, the impact of DMXAA and other VDAs in specifically
radiosensitising HNSCC has not been reported. In relation to targeting hypoxia-induced proteins, the
protein kinase AKT has been shown to be activated under severe hypoxia (0.1% oxygen for 6-72 h) in both
HPV-positive and HPV-negative HNSCC cell lines, and that the AKT inhibitor MK2206 alone significantly
[50]
reduced HPV-positive and HPV-negative HNSCC cell line growth (sensitiser enhancement ratios of ~1.5) .
Interestingly, MK2206 led to increased radiosensitivity of only the HPV-positive HNSCC cell lines under
hypoxic conditions, however the study was limited to analysing the response to a single dose of radiation,
and the molecular basis for this effect is currently unclear. A major problem with the clinical translation of
these and other strategies is the heterogeneity of oxygen tensions within the hypoxic region of the tumour,
where the level of radioresistance also varies. Nevertheless, further studies examining the molecular and
biological impact of different levels of hypoxia on the comparative radiosensitivity of HPV-positive and
HPV-negative HNSCC cell lines and tumours, and ultimately strategies to overcome radioresistance, are
required.

PARP-1
PARP-1 is one of the 17 members of the PARP family, which acts as an important sensor for gaps and SSBs
in the DNA and plays a fundamental role in BER [97,98] . Here, PARP-1 uses NAD to catalyse the synthesis
+
of ADP-ribose chains to itself and also to target residues of specific proteins, which acts as a platform
for DNA repair protein recruitment. PARP1 is, however, also involved in the repair of DSBs via both HR
[99]
and NHEJ . There has been significant interest in PARP-1, and particularly PARP inhibitors, because
of its synthetic lethal partnership with BRCA1/2 mutations in breast cancers [100,101] . Therefore, PARP
inhibitors have been increasingly investigated as a treatment option in HNSCC with some promising
results. Relatively earlier studies focused on veliparib which showed in three HPV-negative HNSCC cell
lines that the inhibitor (at >5 µmol/L) exhibited high cytotoxicity in the presence of ionising radiation, and
was exacerbated with the EGRF inhibitor cetuximab . Similarly, veliparib (at 10 µmol/L) decreased the
[51]