Targeting of Aberrant Signaling in Patient-Derived Colorectal Cancer Models

描述(申请人提供)：本申请的总体目标是培养克洛伊·E·阿特里亚医学博士，他是一名在翻译研究方面具有良好基础的候选人，成为从人体组织衍生的临床前模型中分子靶向抑制物的领先独立研究员，目标是改进转移性结直肠癌(MCRC)患者的治疗。拟议的研究计划包括以下培训目标：1)完善分子靶向治疗方面的综合专业知识，从化学到对细胞信号和性能的影响，在早期试验中；2)在研究中建立使用患者样本的专业知识，包括模型开发、表征和基因组分析；3)获得临床试验设计方面的专业知识，包括生物统计学和相关科学；4)在关键领域，如多学科团队的管理方面实现专业发展。这项拟议的研究将解决阻碍mCRC患者治疗进步的局限性：1)从商业上可获得的CRC细胞系衍生的典型临床前模型中的药物测试未能预测CRC患者的结果；2)单个分子靶向抑制剂的临床疗效一直不佳，可能是因为CRC在两条主要的致癌途径中显示出异常信号。候选人的中心假设是，在CRC中上调的针对两条通路上的关键节点的抑制剂组合将是最有效的，不依赖于基线信号或单一药物的活性。建议的具体目标如下：1)在结直肠癌患者来源的小鼠模型中测试两种致癌途径的联合抑制剂的效果，2)确定耐药机制并开发克服这种耐药性的药理学策略，以及3)确定在结直肠癌患者来源的小鼠模型中观察到的抑制物效应是否在从肿瘤分离的球体培养中概括，并扩大在球体中的药物筛选。候选人的培训和研究计划结合了课程、教程、指导和实践研究经验，这些经验建立在加州大学旧金山分校无与伦比的学术环境中，加州大学旧金山分校是世界著名的转化医学和研究中心，包括海伦·迪勒家庭综合癌症中心，丰富的机构资源，以及良好整合的临床医生和科学家社区。候选人的导师是霍华德·休斯医学研究所的研究员凯文·肖卡特博士，她的多学科咨询委员会包括杰出的科学家、内科和外科肿瘤学家。拟议研究的成功完成将产生令人信服的临床前理由，用于在mCRC生物标记物定义的子集内的患者中测试特定的靶向抑制剂组合。中期目标是开启一项针对CRC的临床试验，作为成功的R01提案的基础。长期目标是建立一个综合的、患者衍生的临床前平台，为同一批患者的治疗决策提供信息，并使更多的mCRC患者存活下来。

DESCRIPTION (provided by applicant): The overall goal of this application is to train Chloe E. Atreya, MD-PhD, a candidate with an excellent foundation for translational research, to become a leading independent investigator of molecularly targeted inhibitors in preclinical models derived from human tissues, with a goal to improve treatments for patients with metastatic colorectal cancer (mCRC). The proposed research plan incorporates the following training goals: 1) to refine integrated expertise in molecularly targeted therapies, from chemistry to effects on cell signaling and performance in early phase trials, 2) to build expertise in use of patient-derived samples in research, including model development, characterization and genomic analysis 3) to acquire expertise in clinical trial design, including biostatistics and correlative science and 4) to attain professional development in key areas such as management of multidisciplinary teams. The proposed research will address limitations that have hindered therapeutic advancements for patients with mCRC: 1) drug testing in typical preclinical models derived from commercially available CRC cell lines has failed to predict outcomes in CRC patients and 2) the clinical efficacy of individual molecularly targeted inhibitors has been underwhelming, likely because CRC exhibits aberrant signaling in two dominant oncogenic pathways. The candidate's central hypothesis is that combinations of inhibitors targeting key nodes in both pathways upregulated in CRC will be maximally effective independent of baseline signaling or single agent activity. The following specific aims are proposed: 1) to test the effect of combining inhibitors of both oncogenic pathways in CRC patient-derived mouse models, 2) to identify mechanisms of drug resistance and to develop pharmacologic strategies to overcome this resistance, and 3) to determine whether the inhibitor effects observed in CRC patient-derived mouse models are recapitulated in spheroid cultures isolated from tumors, and to expand drug screening in spheroids. The candidate's training and research plan incorporates a combination of coursework, tutorials, mentoring, and hand-on research experience set in the unparalleled academic environment of UCSF, a world-renowned center of excellence in translational medicine and research, including the Helen Diller Family Comprehensive Cancer Center, abundant institutional resources, and a well-integrated community of clinicians and scientists. The candidate's mentor is Howard Hughes Medical Institute investigator, Dr. Kevan Shokat, and her multidisciplinary advisory committee includes distinguished scientists, medical and surgical oncologists. Successful completion of the proposed research will produce compelling preclinical rationale for testing specific targeted inhibitor combinations in patients within biomarker-defined subsets of mCRC. The intermediate-term goal is to open a CRC-specific clinical trial that will serve as the basis for a successful R01 proposal. Long- term goal are for the integrated, patient-derived preclinical platform to inform treatment decisions for the same patients from whose tumor cells the models derived, and to result in more survivors of mCRC.