Will develop a dynamic model of response to HER family inhibitors in tumors in which HER2 is amplified that encompasses both fast, phosphorylation-based events (on the order of a few minutes) and slower transcriptional and epigenomic processes (on the order of a few days). This model will eventually enable comparative assessment ofthe relative importance of mechanisms of response and resistance and guide development of combinatorial therapeutic strategies to counter resistance. This project is motivated by observations that responses to trastuzumab and lapatinib are not uniform between patients and are frequently not durable. Work in this CCSB project and the general scientific community suggests several mechanisms that may confer resistance including: (a) activating downstream mutations in the PI3K pathway, (b) microenvironment mediated activation of interacting networks, (c) PI3K mediated changes in HERS expression and signaling and (d) transcriptional feedback regulation from response related network elements. An initial dynamic version ofthe model will be developed in collaboration with the MIT CCSB (see letter of collaboration from Dr. Lauffenburger). The model will differ from existing work in three important ways: it will exploit a mathematical separation of time scales for fast and slow dynamics, incorporate underlying genetic aberrations, and include parallel signaling from the microenvironment. Analysis ofthis initial model will be used to help understand the roles of cooperating genetic aberrations, transcriptional and translational regulation, vesicle control and microenvironment in fast and slow dynamic processes. Subsequent versions of the model will build on experimental measurements of temporal biological and molecular responses of HER2+ breast cancer cell lines to HER2 family signaling network inhibitors administered alone and in combination as well as information from Projects 1, 2 and 4 and from the Stanford CCSB's MYC modeling efforts (see letter of collaboration from Dr. Plevritis). A combination of Bayesian network analysis and dynamic modeling will be used to model the unexplored effects of epigenomic modulation of transcription on HER2/3 signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA112970-10
Application #
8629532
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
Riesco, Adrián; Santos-Buitrago, Beatriz; De Las Rivas, Javier et al. (2017) Epidermal Growth Factor Signaling towards Proliferation: Modeling and Logic Inference Using Forward and Backward Search. Biomed Res Int 2017:1809513
Hassan, Saima; Esch, Amanda; Liby, Tiera et al. (2017) Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer. Mol Cancer Ther 16:2892-2901
Sears, Rosalie; Gray, Joe W (2017) Epigenomic Inactivation of RasGAPs Activates RAS Signaling in a Subset of Luminal B Breast Cancers. Cancer Discov 7:131-133
Hill, Steven M; Nesser, Nicole K; Johnson-Camacho, Katie et al. (2017) Context Specificity in Causal Signaling Networks Revealed by Phosphoprotein Profiling. Cell Syst 4:73-83.e10
Hafner, Marc; Heiser, Laura M; Williams, Elizabeth H et al. (2017) Quantification of sensitivity and resistance of breast cancer cell lines to anti-cancer drugs using GR metrics. Sci Data 4:170166
Seviour, E G; Sehgal, V; Mishra, D et al. (2017) Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p. Oncogene 36:1339-1350
Gendelman, Rina; Xing, Heming; Mirzoeva, Olga K et al. (2017) Bayesian Network Inference Modeling Identifies TRIB1 as a Novel Regulator of Cell-Cycle Progression and Survival in Cancer Cells. Cancer Res 77:1575-1585
Chen, Mo; Peters, Alec; Huang, Tao et al. (2016) Ras Dimer Formation as a New Signaling Mechanism and Potential Cancer Therapeutic Target. Mini Rev Med Chem 16:391-403
Ko, Andrew H; Bekaii-Saab, Tanios; Van Ziffle, Jessica et al. (2016) A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. Clin Cancer Res 22:61-8
Muranen, Taru; Selfors, Laura M; Hwang, Julie et al. (2016) ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP. Cancer Res 76:7168-7180

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