Targeting of Aberrant Signaling in Patient-Derived Colorectal Cancer Models

描述（由申请人提供）：本申请的总体目标是培养具有良好转化研究基础的医学博士候选人Chloe E. Atreya，成为来自人体组织的临床前模型中分子靶向抑制剂的领先独立研究者，目标是改善转移性结直肠癌（mCRC）患者的治疗。拟议的研究计划包括以下培训目标：1)完善分子靶向治疗的综合专业知识，从化学到细胞信号传导和早期试验的表现；2)建立在研究中使用患者来源样本的专业知识，包括模型开发、表征和基因组分析；3)获得临床试验设计的专业知识，包括生物统计学和相关科学；4)在关键领域获得专业发展，如多学科团队的管理。拟议的研究将解决阻碍mCRC患者治疗进展的局限性：1)来自市售CRC细胞系的典型临床前模型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令人印象印象，可能是因为CRC在两种主要的致癌途径中表现出异常信号。候选人的中心假设是，针对CRC中上调的两种通路中的关键节点的抑制剂组合将在独立于基线信号或单一药物活性的情况下最大限度地有效。本文提出了以下具体目标：1)在结直肠癌小鼠模型中测试两种致癌途径的抑制剂联合使用的效果；2)确定耐药机制并制定克服这种耐药的药理学策略；3)确定在结直肠癌小鼠模型中观察到的抑制剂效应是否在肿瘤分离的球形培养物中重现，并扩大在球形培养物中的药物筛选。候选人的培训和研究计划将在UCSF无与伦比的学术环境中结合课程、辅导、指导和实践研究经验，UCSF是世界知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，以及一个由临床医生和科学家组成的良好社区。候选人的导师是霍华德休斯医学研究所的研究员Kevan Shokat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为在生物标志物定义的mCRC亚群患者中测试特定靶向抑制剂组合提供令人信服的临床前理论依据。中期目标是开展一项针对crc的临床试验，作为成功的R01申请的基础。长期目标是建立一个综合的、患者衍生的临床前平台，为模型衍生肿瘤细胞的同一患者提供治疗决策，并导致更多的mCRC幸存者。

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.