We propose using Positron Emission Tomography (PET) based molecular imaging of key molecules andbiochemical pathways implicated in the abnormal proliferation and treatment failure of castrate resistantmetastatic prostate cancer, the lethal variant of the disease. Studies planned are interdisciplinary andtranslational: collaboration for basic studies is with Dr.s N. Rosen/D. Solit (Molecular Oncogenesis Lab.) andfor clinical studies with Dr.s H. Scher/M. Morris (GU Oncology). This project is a continuation of project 4 inthe MSKCC ICMIC P50 CA86438. In this competitive renewal, we will refine the androgen receptor (AR),her2 receptor (her2) and heat shock protein 90 (HSP90) imaging methods that were previously invented ordeveloped under ICMIC. Our focus on these molecular imaging methods is based on the biologic linksbetween these 3 molecules including the key role of AR in castrate-resistant prostate cancer and the clinicalpotential of her2, HSP90 and histone deacetylase (HDAC) inhibitor drugs for therapy of prostate and othermajor cancers.
In specific aim 1 A, we will develop a kinetic-method for quantification of AR using [18F] 16Bdihydrotestosterone (FDHT) in castrate resistant prostate cancer, with the rationale that this will improvetreatment selection and monitoring for drugs which target AR. Based on our prior findings, in specific aim1B, we propose a medicinal chemistry path to improve AR radioligands, through addition of appropriateside chains, to retard metabolite formation and increase AR binding affinity.
In specific aim 2, we continuedevelopment of her2 targeting based on PET labeled antibody forms of herceptin IgG, fab'2, and fab'.
In specific aim 3, we will explore the potential of lodine-124 labeled purine based HSP90 inhibitors as imagingagents for HSP90.
In specific aim 4, we will continue to optimize clinical imaging paradigms of thepharmacodynamic effects of therapies for castrate resistant prostate cancer, using FDHT, FDG, C-11methionine, and F-18 L-Thymidine (FLT). Clinical protocols are planned in prostate cancer for drugs whichare known to inhibit AR, HSP90 and her2 molecules, such as the AR targeting agents, ansamycin andpurine based HSP90 inhibitors, herceptin and the HDAC inhibitors. In summary, building on our priorresearch, we plan to continue the process of discovery, development and translation of molecular imagingmethods into advanced practice leading to improved diagnosis and therapy in human prostate cancer.
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