This response to PAR-04-069, is a renewal application based on work begun during the original period of ICMIC funding at MSKCC The central theme of this new proposal is translation of the progress we have made into clinical research and application in oncology. Two focus areas are proposed which build on the success of the past funding period: a) human reporter gene constructs will be developed and used to study and better understand T cell interactions and activation in adoptive T cell therapy in patients, (Projects 1 and 2), and b) molecular imaging of the key molecules relevant to assessing drug treatment response, particularly for signal transduction inhibitors, and especially in solid tumors (Projects 3-5). Reporter gene imaging applications in adoptive cell therapy, including targeting of CD4 and CDS sub-types and chimeric Tcells with T-cells with artificial reactivity to prostate cancer, will be studied in man using human derived reporter genes (P1 and P2): Imaging T cell interactions in adoptive therapy of EBV-associated lymphoma (R. Blasberg, Project 1 leader;R. O'Rielly, co-leader), and PET imaging of survival, activation, and response to cytokine stimulation of genetically retargeted prostate specific T cells (V. Ponomarev, Project 2 leader;M. Sadelain, co-leader). In Project 3, high field MRI/MRS will probe the pharmacodynamics of in vivo drug conversion and metabolism, to predict sensitivity for an important new class of angiogenesis inhibitors, and to develop of non-invasive markers (J. Koutcher, Project 3 leader). In Projects 4 and 5, Positron Emission Tomography (PET) based molecular imaging methods will study the biology of treatment response, using novel radioligands for aridrogen receptor, her2, and heat shock protein 90. The development of methodologies for the in vivo imaging of the effects of novel inhibitors of signal transduction for translation to the clinic (N. Rosen, Project 3 leader;D. Solit, co-leader), and molecular imaging of castrate-resistant metastatic prostate cancer (S. Larson, Project 5 leader;H. Scher and P. Smith-Jones, coleaders). Translational developmental projects, oncology based career development, and molecular biology, radiochemistry/cyclotron and data analysis research resources provide essential infrastructure. In summary, novel molecular imaging paradigms will be used to address important clinical questions in oncology.
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