The overall objective of this proposal is to use magnetic resonance imaging (MRI) to evaluate the efficacy of novel experimental therapeutics against genetically engineered mouse (GEM) models of gliomas. Two different models will be evaluated which include the PDGF-driven oligodendroglioma and the Ras+ Akt-driven glioblastoma multiforme models. Alterations in different signaling pathways produce these two distinct tumor types, thus we hypothesize that these different tumors will elicit a different therapeutic response to the specific combinations of small molecules to be evaluated in this proposal Induction of tumors will be accomplished using our GEM models followed by MRI-selection of tumors for inclusion in the therapeutic trials. Quantitative assessment of therapeutic outcomes will be accomplished using both TI-, T2-, and diffusion-weighted multislice MRI. Each animal will serve as its own control which will offer the distinct advantage of noninvasively determining both cell kill values and changes in tumor water diffusion coefficient (ADC) values as quantitative endpoints of therapeutic efficacy. Histological evaluation of therapeutic effects will also be accomplished on harvested tumor tissue. This proposal will be accomplished by a close collaboration between Memorial Sloan-Kettering Cancer Center (MSKCC) and Molecular Therapeutics (MRx), a company proficient in pre-clinical noninvasive imaging of mouse cancer models MSKCC will provide the producer cell lines, will assist with establishing the necessary protocols for MRx scientists to initiate the tumor models, and will design the pre-clinical trials including procurement of the therapeutic agents to be evaluated MRx will house the GEM models for pre-clinical iherapeutic studies. Tumors will be induced using MSKCC-provided producer cell lines and animals will be imaged over time to identify animals with tumors for inclusion into the therapeutic trial. All of the digital MRI data will undergo digital image post-processing to generate quantitative 3-dimensional tumor volumes and ADC maps over time. These will be used to calculate pre- and post-tumor growth kinetics and log (cell kill) values MSKCC will also be responsible for the processing and pathological interpretation of the brain tissues as well as well as their correlation to the processed digital MRI data forwarded from MRx.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA099489-02
Application #
6730649
Study Section
Special Emphasis Panel (ZRG1-ET-1 (02))
Program Officer
Mietz, Judy
Project Start
2003-04-01
Project End
2008-01-31
Budget Start
2004-03-04
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$490,293
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Hambardzumyan, Dolores; Squatrito, Massimo; Carbajal, Eletha et al. (2008) Glioma formation, cancer stem cells, and akt signaling. Stem Cell Rev 4:203-10
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Shih, Alan H; Holland, Eric C (2006) Notch signaling enhances nestin expression in gliomas. Neoplasia 8:1072-82
Momota, Hiroyuki; Nerio, Edward; Holland, Eric C (2005) Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65:7429-35

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