Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand.
Cells. 2019 Jul 13;8(7):717. doi: 10.3390/cells8070717.
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-, , and -did not strongly influence evofosfamide sensitivity in univariate analyses, although a weak significant relationship with was observed, while 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.
肿瘤缺氧是头颈部鳞状细胞癌 (HNSCC) 预后不良和放化疗失败的标志物，为该治疗环境下的治疗干预提供了策略。为了评估缺氧激活前药依氟鸟氨酸（TH-302）在 HNSCC 中的应用，我们建立了 10 个早期传代的患者衍生异种移植（PDX）HNSCC 模型，这些模型通过其组织病理学、缺氧状态、基因表达和对依氟鸟氨酸的敏感性进行了特征描述。所有 PDX 模型都与它们源自的患者肿瘤的组织学非常相似。结合报告的 HNSCC 临床值，匹莫硝唑阳性肿瘤缺氧分数范围为 1.7-7.9%，而 Toustrup 缺氧基因特征的 mRNA 表达表明 PDX 与匹配的患者肿瘤之间存在密切相关性，共同表明 PDX 模型可能准确地模拟临床肿瘤缺氧。依氟鸟氨酸作为单一药物（50mg/kg IP，qd×5 连续三周）在 PDX 模型中表现出抗肿瘤疗效，疗效各不相同，从一个 p16 阳性 PDX 模型的完全消退到三个最耐药模型中缺乏明显的活性。尽管所有 PDX 模型均显示出肿瘤缺氧的证据，并且缺氧对依氟鸟氨酸的激活至关重要，但依氟鸟氨酸的抗肿瘤活性与匹莫硝唑免疫组化确定的肿瘤缺氧状态仅呈弱相关性。其他候选依氟鸟氨酸敏感性基因、、和在单变量分析中并未强烈影响依氟鸟氨酸的敏感性，尽管观察到与的关系较弱，而在 PDX 肿瘤中则丧失了的表达。总体而言，这些数据证实依氟鸟氨酸在临床上相关的 HNSCC PDX 肿瘤模型中具有抗肿瘤活性，并支持进一步在 HNSCC 患者中评估该药。需要进一步研究以确定除缺氧外还能影响对依氟鸟氨酸敏感性的因素，并将其作为支持依氟鸟氨酸在 HNSCC 精准医学治疗中应用的预测生物标志物。
