Abstract
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.
Highlights
Hypoxia, a deficiency in oxygen in tissues, arises selectively in tumours through inefficient blood flow and oxygen delivery as a result of the irregular and dysfunctional vasculature that forms as tumours grow [1,2,3], as well as through oxygen consumption in tumours [4,5] and adaptations to survive under severe hypoxia [6]
The evidence supporting hypoxia as an oncology target is strongest in head and neck squamous cell carcinoma (HNSCC), where hypoxia is a marker of poor prognosis and failure of chemoradiotherapy [20,21,22,23,24]
Eleven of the tumour specimens grew as first generation (P1) patient-derived xenograft (PDX) tumours in mice, for a take rate of 61%
Summary
A deficiency in oxygen in tissues, arises selectively in tumours through inefficient blood flow and oxygen delivery as a result of the irregular and dysfunctional vasculature that forms as tumours grow [1,2,3], as well as through oxygen consumption in tumours [4,5] and adaptations to survive under severe hypoxia [6]. Hypoxic cells are resistant to radiotherapy, which requires oxygen to induce DNA double-strand breaks [1] and to many chemotherapy drugs through multiple mechanisms including cell cycle arrest [12], protection from apoptosis [13,14], and limited penetration into hypoxic regions of tumours [15,16]. The evidence supporting hypoxia as an oncology target is strongest in head and neck squamous cell carcinoma (HNSCC), where hypoxia is a marker of poor prognosis and failure of chemoradiotherapy [20,21,22,23,24]. For HPV-negative disease, patient survival has not markedly improved in recent decades and is limited by locoregional failure, metastases, and resistance to therapy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
