Tumour
hypoxia is a marker of poor prognosis and failure of
chemoradiotherapy in
head and neck squamous cell carcinoma (
HNSCC), providing a strategy for therapeutic intervention in this setting. To evaluate the utility of the
hypoxia-activated
prodrug evofosfamide (TH-302) in
HNSCC, we established ten early passage patient-derived xenograft (PDX) models of
HNSCC that were characterised by their histopathology,
hypoxia status, gene expression, and sensitivity to
evofosfamide. All PDX models closely resembled the histology of the patient tumours they were derived from.
Pimonidazole-positive tumour hypoxic fractions ranged from 1.7-7.9% in line with reported
HNSCC clinical values, while
mRNA expression of the Toustrup
hypoxia gene signature showed close correlations between PDX and matched patient tumours, together suggesting the PDX models may accurately model clinical tumour
hypoxia.
Evofosfamide as a single agent (50 mg/kg IP, qd × 5 for three weeks) demonstrated antitumour efficacy that was variable across the PDX models, ranging from complete regressions in one p16-positive PDX model to lack of significant activity in the three most resistant models. Despite all PDX models showing evidence of tumour
hypoxia, and
hypoxia being essential for activation of
evofosfamide, the antitumour activity of
evofosfamide only weakly correlated with tumour
hypoxia status determined by
pimonidazole immunohistochemistry. Other candidate
evofosfamide sensitivity genes-MKI67, POR, and SLFN11-did not strongly influence
evofosfamide sensitivity in univariate analyses, although a weak significant relationship with MKI67 was observed, while SLFN11 expression was lost in PDX tumours. Overall, these data confirm that
evofosfamide has antitumour activity in clinically-relevant PDX tumour models of
HNSCC and support further clinical evaluation of this drug in
HNSCC patients. Further research is required to identify those factors that, alongside
hypoxia, can influence sensitivity to
evofosfamide and could act as predictive
biomarkers to support its use in
precision medicine therapy of
HNSCC.