Germ-line miRNA binding site variants as biomarkers of toxicity and response to checkpoint inhibition

种系 miRNA 结合位点变异作为毒性和检查点抑制反应的生物标志物

• 批准号: 10393650
• 负责人: Joanne B Weidhaas
• 金额: $ 36.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393650
• 关键词: 3' Untranslated Regions; Address; Binding Sites; Biological Markers; Biology; Cancer Control; Cancer Patient; Cells; Clinical Trials; Code; Combined Modality Therapy; Communication; Complex; DNA; DNA Repair; DNA analysis; Data; Fibrosis; Future; Gene Expression; Genome; Germ Lines; Germ-Line Mutation; Goals; Head and Neck Squamous Cell Carcinoma; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunotherapy; KRAS2 gene; Knowledge; Lead; Libraries; Light; Mediating; MicroRNAs; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; Patients; Persons; Phase I/II Clinical Trial; Proteins; Radiation; Radiation therapy; Regulator Genes; Role; Sampling; Source; T-Lymphocyte; Technology; Tissues; Toxic effect; Treatment-related toxicity; Tumor-infiltrating immune cells; Untranslated RNA; Variant; anti-CTLA-4 therapy; anti-PD-1; anti-PD-L1 therapy; base; biological adaptation to stress; cancer care; cancer therapy; checkpoint inhibition; checkpoint therapy; chemotherapy; experience; genome wide association study; immune checkpoint blockade; immune-related adverse events; immunomodulatory therapies; improved; interest; novel; patient response; patient subsets; personalized approach; personalized cancer therapy; personalized medicine; predictive marker; prospective; radiation response; response; response biomarker; side effect; targeted biomarker; treatment response; tumor

PROJECT SUMMARY There is an incredible, desperate need to find new biomarkers to improve our ability to personalize cancer therapy, to identify responders, and, perhaps more importantly, to identify those that will experience toxicity from treatment in the context of response and non-response. This need has led to Provocative Question #8, asking us to investigate: What are the predictive biomarkers for the onset of immune-related adverse events associated with checkpoint inhibition, and are they related to markers for efficacy? While there have been several tumor-acquired mutations applied as biomarkers for targeted chemotherapies, no such biomarkers have been identified that can predict toxicity to therapy. Immune-related adverse events are likely related to the complex host-specific response to therapy, suggesting that the host's tumor may not be the best source of biomarkers, but that instead germ-line biomarkers, that are also present in all the patient's cells, including their immune cells, could be a much more viable source. While global approaches to study normal DNA have been applied to find germline biomarkers, they do not purport to identify functional biomarkers, only tagging SNPs that may be associated with functional biomarkers elsewhere in the DNA. There is growing evidence that germline microRNA (miRNA) disrupting mutations are in fact functional biomarkers identifying patients with altered stress responses to cancer therapy, which are not currently included in normal DNA analyses. In this proposal, the goal is to validate the predictive power of this new class of miRNA-based biomarkers, in two clinical trials of patients with NSCLC or HNSCC, treated with immune therapies. The final confirmed panel of functional biomarkers will be further correlated with other biomarkers found to help identify patients with toxicity to checkpoint therapy. Results from this proposal could allow the identification of patients who have genetically unique immune system circuitry resulting in an altered response to immune modulating therapies, which will allow significant progress towards answering PQ#8.

项目总结 人们迫切需要找到新的生物标记物来提高我们个性化癌症的能力 治疗，以确定响应者，也许更重要的是，确定那些将经历毒性的人 在应答者和无应答者的情况下进行治疗。这种需要导致了挑衅性的问题#8， 要求我们调查：免疫相关不良事件发生的预测生物标志物是什么 与检查点抑制相关，它们是否与疗效标记物相关？ 虽然已经有几个肿瘤获得性突变被用作靶向化疗的生物标记物， 目前还没有发现这样的生物标志物可以预测治疗的毒性。免疫相关不良事件 很可能与复杂的宿主特异性治疗反应有关，这表明宿主的肿瘤可能不是 最好的生物标记物来源，但不是生殖系生物标记物，也存在于所有患者的 细胞，包括它们的免疫细胞，可能是一个更可行的来源。 虽然研究正常DNA的全球方法已经被应用于寻找生殖系生物标记物，但它们并没有 声称识别功能生物标记物，只标记可能与功能生物标记物相关的SNP 在DNA的其他地方。越来越多的证据表明，生殖系微小RNA(MiRNA)破坏突变是在 识别癌症治疗应激反应改变的患者的功能生物标志物，而不是 目前包括在正常的DNA分析中。在这份提案中，目标是验证这一预测能力 在NSCLC或HNSCC患者的两项临床试验中，新的一类基于miRNA的生物标记物， 免疫疗法。最终确认的功能生物标志物小组将进一步与其他 发现的生物标记物有助于识别对检查点治疗有毒性的患者。这项提案的结果可能是 允许识别具有遗传独特免疫系统回路导致改变的患者 对免疫调节疗法的反应，这将使回答PQ#8方面取得重大进展。