Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America.
PLoS One. 2019 Oct 9;14(10):e0223639. doi: 10.1371/journal.pone.0223639. eCollection 2019.
Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.
头颈部鳞状细胞癌（HNSCC）仍然是一种预后不良的疾病，其治疗方法通常会导致患者的进食和说话等关键功能永久受损。目前，仅有三种靶向疗法获得美国食品和药物管理局（FDA）批准用于 HNSCC，其中两种是最近批准的免疫疗法。在这项工作中，我们确定了与这种疾病相关的生物学途径，这些途径可能成为目前 FDA 批准的癌症药物的靶点，从而扩大 HNSCC 治疗中潜在治疗方法的范围。我们分析了来自基因组数据共享（GDC）数据库的 508 例 HNSCC 患者的测序信息，并评估了哪些生物学途径在体细胞突变或拷贝数改变方面存在显著富集。然后，我们使用癌症靶标组（Cancer Targetome），这是一个药物靶点信息的汇编，将途径进一步分类为“轻”或“暗”途径。“轻”途径在体细胞突变（或拷贝数改变）方面具有统计学意义的富集，并包含一个或多个当前 FDA 批准的癌症药物的靶点，而“暗”途径在体细胞突变（或拷贝数改变）方面富集，但目前不受 FDA 批准的癌症药物的靶向作用。我们的分析表明，大约 35-38%的疾病特异性途径在重新利用当前癌症药物方面具有潜力。我们根据 HPV 状态进一步评估了患者肿瘤样本中“轻”和“暗”途径。HNSCC 富集生物学途径的“轻”和“暗”途径框架使我们能够根据 HNSCC 遗传景观和 FDA 批准的癌症药物信息，更好地为 HNSCC 的靶向治疗确定优先级，以进行进一步研究。我们还强调了识别亚途径的重要性，这些亚途径可能对靶向治疗和交叉靶向治疗最有益，以预测与潜在临床意义相关的阳性或阴性协同作用。该框架非常适合精准药物组开发，以及确定具有高度异常、未靶向的候选药物，以用于未来的药物开发。
