Mechanisms of resistance to MEK Inhibition in RAS-pathway activated chronic myelomonocytic leukemia

项目摘要/摘要 概述：该奖项的目标是为阿米·帕特尔博士提供培训和指导研究经验 以确保她成功地过渡到一名在生物学和治疗方面具有专业知识的独立调查员 髓系恶性肿瘤。Patel博士的长期目标是创建和支持一个独立的基于 致力于研究髓系肿瘤靶向耐药性的翻译研究计划。 研究：慢性粒单核细胞白血病(CMML)是一种侵袭性血液系统恶性肿瘤，与 令人沮丧的生存结果和低的治疗潜力。治疗选择极其有限，耐受性很差 而且未能解决许多与疾病相关的症状。靶向药物代表了一种很有前途的治疗方法 突变导致RAS/有丝分裂原异常信号转导的CMML患者的机会 活化的激酶(MAPK)途径。拟议的研究旨在了解CMML的这个子集是否 患者可以受益于cobimetinib的治疗，cobimetinib是一种RAS/MAPK信号的特异性抑制剂。这项建议 包括一项临床试验，以测试cobimetinib对RAS/MAPK激活的CMML患者的疗效。 不幸的是，靶向抑制剂的临床经验支持最终出现耐药性。 这项拟议的研究旨在了解、预防和克服预期的MEK抑制剂耐药性。 科比美替尼试验患者的纵向样本将使用完整的外显子组和RNA进行分析 对耐药的生物标记物进行测序。基于实验室的临床前研究将利用先进的 细胞系、原代CMML细胞和患者的高通量测序和靶向验证方法 衍生的CMML异种移植模型，以帮助识别可与 临床试验结果。与MEK抑制剂耐药有关的通路可能是靶向抑制的候选者， 导致在RAS激活的CMML中开发新的组合治疗策略。 职业发展：帕特尔博士是一位成就卓著的血液学家和肿瘤学家，在 髓系恶性肿瘤的翻译研究。然而，在启动独立研究项目之前， Patel博士需要在高级测序和生物信息学分析、基因组编辑和 技术和临床试验的实施和监督。结构化的受保护时间、教学方法和 K08提供的指导将使Patel博士能够完成这一基本培训。帕特尔博士已经组装好了 一个经验丰富、多元化和国际公认的指导团队致力于她未来的成功。 亨斯迈癌症研究所，NCI指定的综合癌症中心，以及犹他大学 为Patel博士提供丰富和支持性的制度环境，推动她的事业发展。

PROJECT SUMMARY/ABSTRACT Overview: The goal of this award is to provide Dr. Ami Patel with the training and mentored research experience to ensure success in her transition to an independent investigator with expertise in the biology and treatment of myeloid malignancies. Dr. Patel’s long term goal is to create and support an independent laboratory-based translational research program dedicated to the investigation of targeted drug resistance in myeloid neoplasms. Research: Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy associated with dismal survival outcomes and low curative potential. Treatment options are extremely limited, poorly tolerated and fail to address many disease-related symptoms. Targeted agents represent a promising therapeutic opportunity for CMML patients with mutations that lead to aberrant signal transduction through the RAS/mitogen activated kinase (MAPK) pathway. The proposed research aims to understand whether this subset of CMML patients could benefit from treatment with cobimetinib, a specific inhibitor of RAS/MAPK signaling. The proposal includes a clinical trial to test the efficacy of cobimetinib in CMML patients with RAS/MAPK activation. Unfortunately, clinical experience with targeted inhibitors support the eventual emergence of drug resistance. The proposed research aims to understand, prevent and overcome anticipated MEK inhibitor resistance. Longitudinal samples from patients treated on the cobimetinib trial will be analyzed using whole exome and RNA sequencing to identify biomarkers of drug resistance. Laboratory-based preclinical studies will utilize advanced high throughput sequencing and target validation methodologies in cell lines, primary CMML cells and patient derived xenograft models of CMML to help identify mechanisms of resistance that can be cross-referenced with clinical trial findings. Pathways implicated in MEK inhibitor resistance may be candidates for targeted inhibition, leading to the development of novel combinatorial treatment strategies in RAS-activated CMML. Career Development: Dr. Patel is an accomplished hematologist-oncologist with a strong background in translational research in myeloid malignancies. However, prior to starting an independent research program, Dr. Patel requires further training in advanced sequencing and bioinformatics analysis, genome editing and techniques and clinical trial implementation and oversight. The structured protected time,didactics and mentoring provided by the K08 will allow Dr. Patel to complete this essential training. Dr. Patel has assembled a highly experienced, diverse and internationally-recognized mentoring team committed to her future success. The Huntsman Cancer Institute, an NCI-designated Comprehensive Cancer Center, and the University of Utah provide a rich and supportive institutional environment for Dr. Patel to advance her career.