German Cancer Research Center (DKFZ) Heidelberg, Division of Radiooncology Radiobiology, Germany.
German Cancer Research Center (DKFZ) Heidelberg, Division of Radiooncology Radiobiology, Germany; German Cancer Research Center (DKFZ) Heidelberg, Division of Applied Bioinformatics, Germany; Faculty for Mathematics and Computer Science, Heidelberg University, Germany; HIDSS4Health - Helmholtz Information and Data Science School for Health, Karlsruhe/Heidelberg, Germany.
Radiother Oncol. 2024 Oct;199:110348. doi: 10.1016/j.radonc.2024.110348. Epub 2024 May 31.
Hypoxia remains a challenge for the therapeutic management of head and neck squamous cell carcinoma (HNSCC). The combination of radiotherapy with nimorazole has shown treatment benefit in HNSCC, but the precise underlying molecular mechanisms remain unclear.
To assess and to characterize the transcriptomic/epigenetic landscape of HNSCC tumor models showing differential therapeutic response to fractionated radiochemotherapy (RCTx) combined with nimorazole.
MATERIALS/METHODS: Bulk RNA-sequencing and DNA methylation experiments were conducted using untreated and treated HNSCC xenografts after 10 fractions of RCTx with and without nimorazole. These tumor models (FaDu, SAS, Cal33, SAT and UT-SCC-45) previously showed a heterogeneous response to RCTx with nimorazole. The prognostic impact of candidate genes was assessed using clinical and gene expression data from HNSCC patients treated with primary RCTx within the DKTK-ROG.
Nimorazole responder and non-responder tumor models showed no differences in hypoxia gene signatures However, non-responder models showed upregulation of metabolic pathways. From that, a subset of 15 differentially expressed genes stratified HNSCC patients into low and high-risk groups with distinct outcome.
In the present study, we found that nimorazole non-responder models were characterized by upregulation of genes involved in Retinol metabolism and xenobiotic metabolic process pathways, which might contribute to identify mechanisms of resistance to nitroimidazole compounds and potentially expand the repertoire of therapeutic options to treat HNSCC.
缺氧仍然是头颈部鳞状细胞癌（HNSCC）治疗管理的挑战。放疗联合尼莫唑胺已显示出对 HNSCC 的治疗益处，但确切的潜在分子机制仍不清楚。
评估和描述显示对尼莫唑胺联合分割放化疗（RCTx）治疗反应不同的 HNSCC 肿瘤模型的转录组/表观遗传图谱。
材料/方法：使用未经处理和经 10 次 RCTx 加和不加尼莫唑胺处理的 HNSCC 异种移植物进行批量 RNA-seq 和 DNA 甲基化实验。这些肿瘤模型（FaDu、SAS、Cal33、SAT 和 UT-SCC-45）先前对 RCTx 联合尼莫唑胺表现出异质性反应。使用来自 DKTK-ROG 中接受原发性 RCTx 治疗的 HNSCC 患者的临床和基因表达数据评估候选基因的预后影响。
尼莫唑胺反应者和非反应者肿瘤模型在缺氧基因特征上没有差异。然而，非反应者模型显示代谢途径的上调。由此，一组 15 个差异表达基因将 HNSCC 患者分为低风险和高风险组，具有不同的结局。
在本研究中，我们发现尼莫唑胺非反应者模型的特征是参与视黄醇代谢和外源代谢过程途径的基因上调，这可能有助于确定对硝基咪唑化合物的耐药机制，并可能扩大治疗 HNSCC 的治疗选择范围。
