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

基本信息

批准号：
10653819
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653819
关键词：
3&apos Untranslated Regions Address Binding Sites Biological Markers Biology CTLA4 gene 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-Line Mutation Goals Head and Neck Squamous Cell Carcinoma Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunologic Stimulation Immunotherapy KRAS2 gene Knowledge Lead Libraries Localized Malignant Neoplasm 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 Untranslated RNA Variant anti-CTLA-4 therapy anti-PD-1 anti-PD-L1 therapy biological adaptation to stress biomarker identification cancer care cancer therapy checkpoint inhibition checkpoint therapy chemotherapy experience genome wide association study immune cell infiltrate immune checkpoint blockade immune-related adverse events immunomodulatory therapies immunoregulation 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

项目摘要

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.

项目摘要不可思议，迫切需要寻找新的生物标志物来提高我们个性化癌症的能力治疗，确定反应者，也许更重要的是，确定那些会经历毒性的人从反应和无响应的背景下进行治疗。这种需求导致了挑衅性问题＃8，要求我们调查：与免疫相关事件发作的预测生物标志物是什么与检查点抑制相关，并且它们与功效标记有关吗？虽然有几种肿瘤可获得的突变作为靶向化学疗法的生物标志物，但尚未发现可以预测治疗毒性的这种生物标志物。免疫相关的不良事件可能与复杂的宿主特异性反应有关，表明宿主的肿瘤可能不是生物标志物的最佳来源，而是种系生物标志物，它们也存在于所有患者的包括其免疫细胞在内的细胞可能是更可行的来源。虽然已应用了全球研究正常DNA的方法来查找生殖线生物标志物，但它们却没有旨在识别功能性生物标志物，仅标记可能与功能生物标志物相关的SNP 在DNA中的其他地方。越来越多的证据表明种系microRNA（miRNA）破坏突变事实功能性生物标志物鉴定出压力反应改变对癌症治疗的患者，这不是目前包括在正常的DNA分析中。在此提案中，目标是验证该提议的预测能力在两项NSCLC或HNSCC患者的临床试验中，新的基于miRNA的生物标志物免疫疗法。最终确认的功能生物标志物将进一步与其他相关生物标志物发现有助于鉴定对检查点疗法毒性的患者。该提议的结果可能允许鉴定具有遗传独特的免疫系统电路的患者，导致改变对免疫调节疗法的反应，这将允许回答PQ＃8的重大进展。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prediction of Radiation Treatment Response for Locally Advanced Rectal Cancer via a Longitudinal Trend Analysis Framework on Cone-Beam CT.

DOI：
10.3390/cancers15215142
发表时间：
2023-10-25
期刊：
CANCERS
影响因子：
5.2
作者：
Li, Zirong;Raldow, Ann C.;Weidhaas, Joanne B.;Zhou, Qichao;Qi, X. Sharon
通讯作者：
Qi, X. Sharon

High Recurrence for HPV-Positive Oropharyngeal Cancer With Neoadjuvant Radiation Therapy to Gross Disease Plus Immunotherapy: Analysis From a Prospective Phase Ib/II Clinical Trial.

HPV 阳性口咽癌采用新辅助放疗加免疫疗法治疗的高复发率：来自前瞻性 Ib/II 期临床试验的分析。

DOI：
10.1016/j.ijrobp.2023.04.029
发表时间：
2023
期刊：
International journal of radiation oncology, biology, physics
影响因子：
0
作者：
Ma,TingMartin;Wong,DeborahJ;Chai-Ho,Wanxing;Mendelsohn,Abie;StJohn,Maie;Abemayor,Elliot;Chhetri,Dinesh;Sajed,Dipti;Dang,Audrey;Chu,Fang-I;Xiang,Michael;Savjanji,Ricky;Weidhaas,Joanne;Steinberg,MichaelL;Cao,Minsong;Kishan,
通讯作者：
Kishan,

Identifying MicroRNA Pathway Variants as Biomarkers of Patient Selection for Immune Therapy.

识别 MicroRNA 通路变异作为免疫治疗患者选择的生物标志物。