Tumour hypoxia promotes poor patient outcomes, with particularly strong evidence for head and neck squamous cell carcinoma (HNSCC). To effectively target hypoxia, therapies require selection biomarkers and preclinical models that can accurately model tumour hypoxia. We established 20 patient‐derived xenograft (PDX) and cell line‐derived xenograft (CDX) models of HNSCC that we characterised for their fidelity to represent clinical HNSCC in gene expression, hypoxia status and proliferation and that were evaluated for their sensitivity to hypoxia‐activated prodrugs (HAPs). PDX models showed greater fidelity in gene expression to clinical HNSCC than cell lines, as did CDX models relative to their paired cell lines. PDX models were significantly more hypoxic than CDX models, as assessed by hypoxia gene signatures and pimonidazole immunohistochemistry, and showed similar hypoxia gene expression to clinical HNSCC tumours. Hypoxia or proliferation status alone could not determine HAP sensitivity across our 20 HNSCC and two non‐HNSCC tumour models by either tumour growth inhibition or killing of hypoxia cells in an ex vivo clonogenic assay. In summary, our tumour models provide clinically relevant HNSCC models that are suitable for evaluating hypoxia‐targeting therapies; however, additional biomarkers to hypoxia are required to accurately predict drug sensitivity.

中文翻译：

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头颈癌肿瘤模型中缺氧生物标志物的临床相关性和治疗预测能力

肿瘤缺氧会导致患者预后不良，尤其是头颈鳞状细胞癌 (HNSCC) 的有力证据。为了有效地针对缺氧，治疗需要选择能够准确模拟肿瘤缺氧的生物标志物和临床前模型。我们建立了 20 个 HNSCC 患者来源的异种移植物 (PDX) 和细胞系来源的异种移植物 (CDX) 模型，我们对其特征是其在基因表达、缺氧状态和增殖方面代表临床 HNSCC 的保真度，并评估了它们对缺氧的敏感性。活化的前药（HAP）。PDX 模型对临床 HNSCC 的基因表达表现出比细胞系更高的保真度，CDX 模型相对于其配对细胞系也是如此。通过缺氧基因特征和哌莫硝唑免疫组织化学评估，PDX 模型明显比 CDX 模型缺氧，并且显示出与临床 HNSCC 肿瘤相似的缺氧基因表达。仅缺氧或增殖状态无法通过肿瘤生长抑制或杀死缺氧细胞来确定我们的 20 个 HNSCC 和两个非 HNSCC 肿瘤模型的 HAP 敏感性。离体克隆形成测定。总之，我们的肿瘤模型提供了临床相关的 HNSCC 模型，适合评估缺氧靶向治疗；然而，需要额外的缺氧生物标志物才能准确预测药物敏感性。