This response to PAR-04-069, is a renewal application based on work begun during the original period ofICMIC funding at MSKCC The central theme of this new proposal is translation of the progress we havemade into clinical research and application in oncology. Two focus areas are proposed which build on thesuccess of the past funding period: a) human reporter gene constructs will be developed and used to studyand better understand T cell interactions and activation in adoptive T cell therapy in patients, (Projects 1and 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 geneimaging applications in adoptive cell therapy, including targeting of CD4 and CDS sub-types and chimeric Tcellswith T-cells with artificial reactivity to prostate cancer, will be studied in man using human derivedreporter 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, andresponse to cytokine stimulation of genetically retargeted prostate specific T cells (V. Ponomarev, Project 2leader; M. Sadelain, co-leader). In Project 3, high field MRI/MRS will probe the pharmacodynamics of in vivodrug 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, PositronEmission Tomography (PET) based molecular imaging methods will study the biology of treatmentresponse, using novel radioligands for aridrogen receptor, her2, and heat shock protein 90. Thedevelopment of methodologies for the in vivo imaging of the effects of novel inhibitors of signal transductionfor translation to the clinic (N. Rosen, Project 3 leader; D. Solit, co-leader), and molecular imaging ofcastrate-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. Insummary, novel molecular imaging paradigms will be used to address important clinical questions inoncology.
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