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.

Public Health Relevance

Metastatic colorectal cancer is the second leading cause of cancer-related deaths in the United States: better therapies are urgently needed. My research project will address this public health need by identifying optimal colorectal cancer biomarker-specific combinations of molecularly targeted inhibitors using an integrated, patient-derived preclinical platform. The goal of this work is to improve therapeutic outcomes for patients with metastatic colorectal cancer in the near future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA175153-02
Application #
8733440
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Perkins, Susan N
Project Start
2013-09-15
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rajaram, Satwik; Heinrich, Louise E; Gordan, John D et al. (2017) Sampling strategies to capture single-cell heterogeneity. Nat Methods 14:967-970
Parikh, Aparna; Atreya, Chloe; Korn, W Michael et al. (2017) Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer. J Natl Compr Canc Netw 15:3-8
Atreya, Chloe E; Yaeger, Rona; Chu, Edward (2017) Systemic Therapy for Metastatic Colorectal Cancer: From Current Standards to Future Molecular Targeted Approaches. Am Soc Clin Oncol Educ Book 37:246-256
Strickler, John H; Loree, Jonathan M; Ahronian, Leanne G et al. (2017) Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer. Cancer Discov :
Atreya, Chloe E; Venook, Alan P (2016) Role of Biologics in Colon Cancer: Still Not Clear. J Oncol Pract 12:1229-1230
Strosberg, J R; Cives, M; Hwang, J et al. (2016) A phase II study of axitinib in advanced neuroendocrine tumors. Endocr Relat Cancer 23:411-8
Fidelman, Nicholas; Kerlan Jr, Robert K; Hawkins, Randall A et al. (2016) Radioembolization with 90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study. J Gastrointest Oncol 7:860-874
Atreya, Chloe E; Greene, Claire; McWhirter, Ryan M et al. (2016) Differential Radiographic Appearance of BRAF V600E-Mutant Metastatic Colorectal Cancer in Patients Matched by Primary Tumor Location. J Natl Compr Canc Netw 14:1536-1543
Song, Eun-Kee; Tai, W M; Messersmith, Wells A et al. (2015) Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model. Int J Cancer 136:1967-75
Atreya, Chloe E; Corcoran, Ryan B; Kopetz, Scott (2015) Expanded RAS: refining the patient population. J Clin Oncol 33:682-5

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