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Targeting of Aberrant Signaling in Patient-Derived Colorectal Cancer Models

患者来源的结直肠癌模型中异常信号传导的靶向

基本信息

批准号：
8487191
负责人：
Chloe E. Atreya
金额：
$ 17.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8487191
关键词：
Address Advisory Committees Antibodies Area BRAF gene Biological Markers Biometry Cancer Etiology Cancer Model Cancer Patient Cancer cell line Cell Line Cell model Cessation of life Chemistry Clinical Trials Clinical Trials Design Colorectal Cancer Combined Modality Therapy Communities Comprehensive Cancer Center Core Biopsy Development Disease Distant Metastasis Doctor of Philosophy Drug resistance Environment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Excision Exhibits Family Foundations Future Genetic Genomics Genotype Goals Growth Hand Human Individual Institutes KRAS2 gene Lead Lesion Medical Medical Oncologist Mentors Metastatic Neoplasm to the Liver Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Mutation Neoplasm Metastasis Nude Mice Oncogenic Operative Surgical Procedures Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Phase Phase II Clinical Trials Phosphatidylinositols Phosphotransferases Pre-Clinical Model Preclinical Drug Evaluation Public Health Refractory Reliance Research Research Personnel Research Project Grants Research Training Resistance Resources Rest Sampling Science Scientist Signal Pathway Signal Transduction Specimen Surgical Oncologist Survivors Testing Therapeutic Time Training Translational Research Tyrosine Kinase Inhibitor United States Work Xenograft procedure base clinical efficacy cohort design drug testing effective therapy experience human tissue improved inhibitor/antagonist kinase inhibitor metastatic colorectal model development mouse model multidisciplinary mutant neoplastic cell pre-clinical prevent receptor research study resistance mechanism response translational medicine tumor tumor growth

项目摘要

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.

描述（由申请人提供）：本申请的总体目标是培训克洛伊E。Atreya，MD-PhD，具有良好的转化研究基础的候选人，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，从化学到对细胞信号传导的影响和早期试验中的性能，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）在来自市售CRC细胞系的典型临床前模型中进行的药物测试未能预测CRC患者的结局，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在两个主要致癌途径中表现出异常信号传导。候选人的中心假设是，靶向CRC中上调的两种途径中的关键节点的抑制剂的组合将最大限度地有效，而不依赖于基线信号传导或单一药剂活性。建议的具体目标如下：1）测试在CRC患者来源的小鼠模型中组合两种致癌途径的抑制剂的效果，2）鉴定耐药性的机制并开发克服这种耐药性的药理学策略，和3）确定在CRC患者来源的小鼠模型中观察到的抑制剂效果是否在从肿瘤分离的球状体培养物中重现，并扩大球状体中的药物筛选。候选人的培训和研究计划结合了课程，辅导，指导和动手研究经验，设置在UCSF无与伦比的学术环境中，UCSF是世界知名的转化医学和研究卓越中心，包括Helen Diller家庭综合癌症中心，丰富的机构资源，以及临床医生和科学家的良好整合社区。候选人的导师是霍华德休斯医学研究所研究员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子集内的患者中测试特定靶向抑制剂组合提供令人信服的临床前依据。中期目标是开展一项CRC特定的临床试验，作为R 01提案成功的基础。长期目标是整合的、患者衍生的临床前平台，为模型所来源的肿瘤细胞的相同患者提供治疗决策，并产生更多的mCRC幸存者。