This application joins two physician-scientist leaders in the use of genetically engineered mouse models (GEMMs) to evaluate the utility of these animals for preclinical studies that can directly impact human clinical trials. We will investigate the biology of therapeutic response in solid tumors with particular interest in the PI3-kinase (PI3K) pathway and cells that are resistant to standard of care treatments. Based on our expertise, we will be comparing and contrasting three tumor types where the PI3K pathway contributes to oncogenesis and therapeutic resistance, namely medulloblastoma, glioma, and prostate cancer. We anticipate similarities and differences between these tumor types and expect all three to be cross-informative. In the first project we will compare several drug combinations to determine optimal strategies for complete blockade of this signaling pathway in these tumors in vivo. The second project will investigate the character of the cells that survive radiation in the case of brain tumors and androgen depletion (castration) in the case of prostate cancer, and determine what role the PI3K pathway plays in their stem-like and resistant properties. In Project 3, we will use these mouse models to determine the impact of additional genomic alterations on treatment response and identify mRNA-based gene expression signatures as predictive biomarkers that could then be taken from the mouse into human trials. Collectively, the three Projects bring together experts in mouse modeling, experimental therapeutics, comparative pathology and translational medicine and provide a fertile environment for developing the careers of several promising young physician-scientists.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Pitter, Kenneth L; Tamagno, Ilaria; Alikhanyan, Kristina et al. (2016) Corticosteroids compromise survival in glioblastoma. Brain 139:1458-71
Wee, Boyoung; Pietras, Alexander; Ozawa, Tatsuya et al. (2016) ABCG2 regulates self-renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells. Sci Rep 6:25956
Pietras, Alexander; Katz, Amanda M; Ekström, Elin J et al. (2014) Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14:357-69
Leder, Kevin; Pitter, Ken; LaPlant, Quincey et al. (2014) Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules. Cell 156:603-616
Halliday, John; Helmy, Karim; Pattwell, Siobhan S et al. (2014) In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift. Proc Natl Acad Sci U S A 111:5248-53
Ozawa, Tatsuya; Riester, Markus; Cheng, Yu-Kang et al. (2014) Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell 26:288-300
Brannon, A Rose; Sawyers, Charles L (2013) ""N of 1"" case reports in the era of whole-genome sequencing. J Clin Invest 123:4568-70
Chen, Yu; Chi, Ping; Rockowitz, Shira et al. (2013) ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med 19:1023-9
Polkinghorn, William R; Parker, Joel S; Lee, Man X et al. (2013) Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 3:1245-53
Arora, Vivek K; Schenkein, Emily; Murali, Rajmohan et al. (2013) Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155:1309-22

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