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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：
9324936
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324936
关键词：
Address Advisory Committees Antibodies Area BRAF gene Biological Markers Biometry Cancer Etiology Cancer Model Cell Line Cell model Cessation of life Chemistry Clinical Trials Clinical Trials Design Colorectal Cancer 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 Human Individual Institutes KRAS2 gene Lesion Medical Medical Oncologist Mentors Metastatic Neoplasm to the Liver Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Molecular Target Mutation Neoplasm Metastasis Nude Mice Oncogenic Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Performance Pharmaceutical Preparations Pharmacology Phase Phosphatidylinositols Phosphotransferases Pre-Clinical Model Preclinical Drug Evaluation Public Health Receptor Protein-Tyrosine Kinases Refractory Research Research Personnel Research Project Grants Resistance Resources Rest Sampling Science Scientist Signal Pathway Signal Transduction Specimen Surgical Oncologist Survivors Testing Therapeutic Time Training Translational Research United States Work Xenograft procedure base clinical efficacy cohort colon cancer cell line colon cancer patients combination cancer therapy design drug testing effective therapy experience hands on research human tissue improved inhibitor/antagonist kinase inhibitor metastatic colorectal model development molecular targeted therapies mouse model multidisciplinary mutant neoplastic cell novel therapeutics outcome prediction pre-clinical prevent research study resistance mechanism response specific biomarkers targeted agent therapy outcome 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养拥有良好转化研究基础的医学博士候选人 Chloe E. Atreya 成为人体组织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。拟议的研究计划包含以下培训目标：1）完善分子靶向治疗的综合专业知识，从化学到早期试验中对细胞信号传导和性能的影响，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）在关键领域实现专业发展，例如管理多学科团队。拟议的研究将解决阻碍转移性结直肠癌患者治疗进展的局限性：1）在源自市售结直肠癌细胞系的典型临床前模型中进行的药物测试未能预测结直肠癌患者的结果；2）单个分子靶向抑制剂的临床疗效并不令人印象深刻，可能是因为结直肠癌在两个主要致癌途径中表现出异常信号传导。候选者的中心假设是，针对 CRC 中上调的两条途径中的关键节点的抑制剂组合将具有最大的有效性，独立于基线信号传导或单药活性。提出以下具体目标：1) 在 CRC 患者来源的小鼠模型中测试两种致癌途径组合抑制剂的效果，2) 确定耐药机制并制定克服这种耐药性的药理学策略，3) 确定在 CRC 患者来源的小鼠模型中观察到的抑制剂作用是否在从肿瘤中分离的球体培养物中重现，并扩大球体中的药物筛选。候选人的培训和研究计划结合了课程作业、辅导、指导和实践研究经验，在加州大学旧金山分校无与伦比的学术环境中进行，加州大学旧金山分校是世界著名的转化医学和研究卓越中心，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研究员 Kevan Shokat 博士，她的多学科顾问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 子集中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原理。中期目标是开展一项针对 CRC 的临床试验，该试验将作为 R01 提案成功的基础。长期目标是建立一个综合的、源自患者的临床前平台，为模型源自其肿瘤细胞的同一患者提供治疗决策信息，并导致更多的转移性结直肠癌幸存者。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systemic Therapy for Metastatic Colorectal Cancer: From Current Standards to Future Molecular Targeted Approaches.

转移性结直肠癌的系统治疗：从当前标准到未来的分子靶向方法。

DOI：
10.1200/edbk_175679
发表时间：
2017
期刊：
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
影响因子：
0
作者：
Atreya,ChloeE;Yaeger,Rona;Chu,Edward
通讯作者：
Chu,Edward

A phase II study of axitinib in advanced neuroendocrine tumors.

阿西替尼治疗晚期神经内分泌肿瘤的 II 期研究。

DOI：
10.1530/erc-16-0008
发表时间：
2016
期刊：
Endocrine-related cancer
影响因子：
3.9
作者：
Strosberg,JR;Cives,M;Hwang,J;Weber,T;Nickerson,M;Atreya,CE;Venook,A;Kelley,RK;Valone,T;Morse,B;Coppola,D;Bergsland,EK
通讯作者：
Bergsland,EK

Role of Biologics in Colon Cancer: Still Not Clear.

生物制剂在结肠癌中的作用：仍不清楚。

DOI：
10.1200/jop.2016.018697
发表时间：
2016
期刊：
Journal of oncology practice
影响因子：
0
作者：
Atreya,ChloeE;Venook,AlanP
通讯作者：
Venook,AlanP

Improving Access to Integrative Oncology Through Group Medical Visits: A Pilot Implementation Project.

通过团体就诊改善综合肿瘤学的可及性：试点实施项目。

DOI：
10.1089/acm.2019.0073
发表时间：
2019
期刊：
Journal of alternative and complementary medicine (New York, N.Y.)
影响因子：
0
作者：
Thompson-Lastad,Ariana;Atreya,ChloeE;Chao,MariaT;Pollak,Christine;Dhruva,Anand;Santana,Trilce;Abrams,DonaldI
通讯作者：
Abrams,DonaldI

Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.

DOI：
10.1002/ijc.29225
发表时间：
2015-04-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Song, Eun-Kee;Tai, W. M.;Messersmith, Wells A.;Bagby, Stacey;Purkey, Alicia;Quackenbush, Kevin S.;Pitts, Todd M.;Wang, Guoliang;Blatchford, Patrick;Yahn, Rachel;Kaplan, Jeffrey;Tan, Aik Choon;Atreya, Chloe E.;Eckhardt, Gail;Kelley, Robin K.;Venook, Alan;Kwak, Eunice L.;Ryan, David;Arcaroli, John J.
通讯作者：
Arcaroli, John J.