Molecular Imaging of Castrate- Resistance Metastatic Prostate Cancer

我们建议使用基于正电子发射断层扫描（PET）的关键分子的分子成像， 与去势抵抗性卵巢癌异常增殖和治疗失败有关的生化途径 转移性前列腺癌，这种疾病的致命变种。计划的研究是跨学科的， 翻译：基础研究的合作是与博士。罗森/D. Solit（分子肿瘤发生实验室）和 与Dr.s H. Scher/M. Morris（GU肿瘤学）。该项目是2004年项目4的延续。 MSKCC ICMIC P50 CA86438。在这次竞争性更新中，我们将完善雄激素受体（AR）， her 2受体（her 2）和热休克蛋白90（HSP 90）成像方法 在ICMIC下开发。我们对这些分子成像方法的关注是基于 包括AR在去势抵抗性前列腺癌中的关键作用和临床意义， Her 2、HSP 90和组蛋白脱乙酰酶（HDAC）抑制剂药物用于治疗前列腺和其他疾病的潜力 主要癌症在具体目标1A中，我们将开发一种使用[18 F] 16 B定量AR的动力学方法 双氢睾酮（FDHT）在去势抵抗性前列腺癌中的作用，其基本原理是这将改善 治疗选择和监测靶向AR的药物。根据我们先前的发现，在特定的目标， 1B，我们提出了一种药物化学途径，通过添加适当的 侧链，以延迟代谢物形成并增加AR结合亲和力。在具体目标2中， 基于PET标记的赫赛汀IgG、fab ′ 2和fab ′的抗体形式开发了her 2靶向。在 具体目标3，我们将探索碘-124标记的基于嘌呤的HSP 90抑制剂作为显像剂的潜力 HSP 90的作用在具体目标4中，我们将继续优化临床成像范例， 使用FDHT、FDG、C-11治疗去势抵抗性前列腺癌的药效学效应 甲硫氨酸和F-18 L-胸苷（FLT）。计划在前列腺癌中使用的药物的临床方案， 已知抑制AR、HSP 90和her 2分子，如AR靶向剂安莎霉素和 基于嘌呤的HSP 90抑制剂、赫赛汀和HDAC抑制剂。总而言之，在我们之前的基础上， 研究，我们计划继续发现，发展和分子成像的翻译过程 方法的先进实践，从而改善了人类前列腺癌的诊断和治疗。

We propose using Positron Emission Tomography (PET) based molecular imaging of key molecules and biochemical pathways implicated in the abnormal proliferation and treatment failure of castrate resistant metastatic prostate cancer, the lethal variant of the disease. Studies planned are interdisciplinary and translational: collaboration for basic studies is with Dr.s N. Rosen/D. Solit (Molecular Oncogenesis Lab.) and for clinical studies with Dr.s H. Scher/M. Morris (GU Oncology). This project is a continuation of project 4 in the 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 or developed under ICMIC. Our focus on these molecular imaging methods is based on the biologic links between these 3 molecules including the key role of AR in castrate-resistant prostate cancer and the clinical potential of her2, HSP90 and histone deacetylase (HDAC) inhibitor drugs for therapy of prostate and other major cancers. In specific aim 1A, we will develop a kinetic-method for quantification of AR using [18F] 16B dihydrotestosterone (FDHT) in castrate resistant prostate cancer, with the rationale that this will improve treatment selection and monitoring for drugs which target AR. Based on our prior findings, in specific aim 1B, we propose a medicinal chemistry path to improve AR radioligands, through addition of appropriate side chains, to retard metabolite formation and increase AR binding affinity. In specific aim 2, we continue development 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 imaging agents for HSP90. In specific aim 4, we will continue to optimize clinical imaging paradigms of the pharmacodynamic effects of therapies for castrate resistant prostate cancer, using FDHT, FDG, C-11 methionine, and F-18 L-Thymidine (FLT). Clinical protocols are planned in prostate cancer for drugs which are known to inhibit AR, HSP90 and her2 molecules, such as the AR targeting agents, ansamycin and purine based HSP90 inhibitors, herceptin and the HDAC inhibitors. In summary, building on our prior research, we plan to continue the process of discovery, development and translation of molecular imaging methods into advanced practice leading to improved diagnosis and therapy in human prostate cancer.