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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
7U01CA141502-05
Application #
8534344
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
Project Start
2009-08-26
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$725,951
Indirect Cost
$167,664
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Leder, Kevin; Pitter, Ken; Laplant, Quincey et al. (2014) Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules. Cell 156:603-16
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
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
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
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
Katz, Amanda M; Amankulor, Nduka M; Pitter, Ken et al. (2012) Astrocyte-specific expression patterns associated with the PDGF-induced glioma microenvironment. PLoS One 7:e32453
Jones, T S; Holland, E C (2012) Standard of care therapy for malignant glioma and its effect on tumor and stromal cells. Oncogene 31:1995-2006
Wee, Boyoung; Charles, Nikki; Holland, Eric C (2011) Animal models to study cancer-initiating cells from glioblastoma. Front Biosci (Landmark Ed) 16:2243-58
Pitter, Kenneth L; Galbán, Craig J; Galbán, Stefanie et al. (2011) Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. PLoS One 6:e14545
Becher, Oren J; Hambardzumyan, Dolores; Walker, Talia R et al. (2010) Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res 70:2548-57

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