The objective of this proposal is to image the responses of tumors to new chemotherapeutic drugs in animals, while they are undergoing experimental treatment, and to develop new noninvasive imaging methods to assess the molecular/biochemical effects on the pathways these drugs were designed to inhibit, at doses that are tolerable in animals. This proposal describes a pilot program for the achievement of these goals. We will specifically use animal models for breast and prostate cancer to study the antitumor effects of a drug derived from geldanamycin; namely, 17-allylarninogeldanamycin (17-AAG). We will use PET scanning with [18F]-fluorodeoxyglucose (FDG) and [124I]-iododeoxyuridine (IUdR) to image the tumor response to the drug, and [18F]-dihydrotestosterone (FDHT) to image changes in the androgen receptor. Effects on glucose utilization and tumor proliferation will be correlated with changes in the physical size and pathological markers of tumor response; in prostate xenografts (LNCaP), androgen receptor imaging with FDHT will also be performed. In collaboration with Project 1 of this P-50 application, we will attempt to image loss of HER2-SHC interactions and inhibition of Ras-dependent signaling by the drug. These results will be correlated with direct measurements of HER2, steroid receptor and Raf degradation and downregulation of D cyclin expression in pathologic specimens. A second objective is to evaluate the use of imaging in determining drug response and to develop methodologies to image inhibition of specific signaling pathways. If successful, these techniques will become an integral component of the preclinical development of the drugs we are studying. It is important to note that the animal imaging studies in Aims 1 and 3 of this proposal are complementary to the imaging studies that will be performed on patients with advanced metastatic prostate cancer, as proposed in Project 4 of this P-50 application. In both projects, one objective is to obtain metabolic (phenotypic) images in order to assess and better understand the progression and response of cancer to new molecular-based treatment modalities.
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