PROJECT 1: Among the causes of death due to cancer, brain tumors are ranked second in the pediatric age group and fourth in middle-aged men. Malignant gliomas have remained uniformly fatal;only 50% of patients survive one year from the time of diagnosis. These stark statistics underscore the urgent need for an early assessment of therapeutic efficacy in these patients. Sensitive and early surrogate predictors of therapeutic outcome for patients would improve care and potentially improve prognosis due to the opportunity to individualize and adjust the treatment to each patient. The central hypothesis of this project is that the effectiveness of therapeutic interventions can be determined prior to tumor shrinkage using appropriate imaging surrogate response markers and that the optimal surrogate for outcome prediction will be dependent upon the therapeutic target. A genetically engineered PDGF-driven transgenic glioma model will be utilized with specific molecular imaging reporters developed in Project #2 and used in this Project (#1) to evaluate cytotoxic, as well as molecularly targeted therapeutic interventions. Therapeutic effects on tumor 1H MR metabolites, tumor perfusion and diffusion will be evaluated against cytotoxic agents (chemotherapy, radiation and chemoradiation) and molecularly targeted agents (a PDGFR tyrosine kinase inhibitor, an Akt inhibitor, an mTOR inhibitor and a MEK inhibitor) to determine the optimal surrogate marker for assessment of treatment response for each class of therapy. The effectiveness of MR for detection of treatment response in brain tumors will be evaluated in two Specific Aims. MR data from tumors will be compared with efficacy determined using animal survival, changes in tumor volume/growth rates, and histology to determine which specific or combined imaging-observable parameter can be utilized as a surrogate marker for predicting therapeutic outcome. These studies will provide the rationale for pairing a specific imaging surrogate marker with a therapeutic intervention in order to obtain the most effective readout of early treatment response. These rodent imaging studies will serve as the basis for translating and evaluating these approaches in the clinic as proposed in Project #3. Pub. Health: Overall, this research effort will provide the rationale for initiation of clinical trials with combinations of molecularly targeted therapies for the treatment of malignant brain tumors. In addition, imaging biomarkers for early assessment of treatment response will be identified and validated which will lead to individualization of patient treatment.
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