Each year approximately 190,000 people in the United States will be diagnosed with a primary or metastatic brain tumor. Brain tumors are the leading cause of solid tumor death in children under age 20 now surpassing acute lymphoblastic leukemia, and are the third leading cause of cancer death in young adults ages 20-39. At present, brain tumors are treated by surgery, radiation therapy and chemotherapy used either individually or in combination. Therapy and clinical outcome for cancers of the central nervous system has not improved significantly in the last three decades. Recent discoveries that provide new insights into the defects in cell signaling that lead to brain tumors are providing an opportunity for the use of molecularly targeted therapeutic drugs. There is an increasing recognition that brain cancer is a disease of molecular pathways that regulate cell growth and division and therefore the field is headed towards customized therapy driven by a rational selection of drug combinations. The key will be to identify which combinations of targeted therapies are most efficacious for each tumor type. Projects 1 and 2 will use a mouse brain tumor model that resembles the human disease with regards to defects in specific signaling pathways, rate of growth as well as histological, immunological and imaging characteristics. The goal of Project 1 is to identify the best non-invasive surrogate MR imaging markers (diffusion, perfusion and proton spectroscopy) for therapeutic efficacy in response to molecularly targeted, traditional, and combination therapies. Successful completion of these aims will significantly impact the design of clinical trials for these novel therapies and combination therapies. Project 2 will investigate the use of noninvasive imaging wherein activation or inhibition of key signaling pathways in cancer can be monitored. These studies will provide unique tools for target validation as well as dose and schedule optimization. Project 1 will also use these tools to validate that the MRI based surrogate marker is faithfully reporting changes in specific signaling pathways in response to targeted agents. These molecularly validated MRI based surrogate markers will then be used in clinical trials of molecularly targeted therapies in Project 3. All three research projects will be supported by four cores, the digital image processing core (Core C), the biostatistics core (Core D) as well as the imaging core (Core B). Overall management of the program project will be accomplished by the administrative core (Core A)
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