Molecular Imaging of Castrate- Resistance Metastatic Prostate Cancer

去势抵抗性转移性前列腺癌的分子影像

• 批准号: 7729472
• 负责人: Steven Mark Larson
• 金额: $ 11.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729472
• 关键词: Affinity; Androgen Receptor; Animal Model; Animals; Ansamycin Antineoplastic Antibiotic; Antibodies; Antineoplastic Agents; Attention; Back; Behavior; Biochemical Pathway; Chemistry; Client; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Condition; Detection; Development; Diagnosis; Disease; Disease Progression; Drug Combinations; Drug Monitoring; ERBB2 gene; Enzymes; Functional Imaging; Goals; Grant; Heat-Shock Proteins 90; Histone Deacetylase Inhibitor; Human; Hydroxysteroid Dehydrogenases; Image; Immunoglobulin G; Individual; Iodine; Kinetics; Label; Laboratories; Lead; Lesion; Ligands; Link; Liver; Lodine; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Metabolic; Metabolism; Metastatic Prostate Cancer; Methionine; Methods; Modeling; Molecular; Monitor; Nude Mice; Patient Selection; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Play; Positron; Positron-Emission Tomography; Process; Prostate; Prostate-Specific Antigen; Purines; Radionuclide Imaging; Research; Resistance; Rifabutin; Roche brand of trastuzumab; Role; Selection for Treatments; Serum; Side; Signal Transduction; Site; Stanolone; Steroids; TNFRSF5 gene; Therapeutic; Thymidine; Toxic effect; Tracer; Translational Research; Translations; Treatment Failure; Variant; base; bone; comparative; imaging probe; improved; in vivo Cellular and Molecular Imaging Centers; inhibitor/antagonist; man; molecular imaging; oncology; protein expression; purine; radioligand; radiotracer; receptor; receptor binding; receptor expression; response; tumor; tumor xenograft; tumorigenesis; uptake

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.

我们建议使用基于正电子的发射断层扫描（PET）的关键分子分子成像和 与castrate抗性异常的增殖和治疗失败有关的生化途径 转移性前列腺癌，该疾病的致命变异。计划的研究是跨学科的， 翻译：基础研究协作是与S. N. Rosen博士/D的合作。孤子（分子肿瘤发生实验室）和 用于H. Scher博士/M博士进行临床研究。莫里斯（GU肿瘤学）。该项目是项目4的延续 MSKCC ICMIC P50 CA86438。在这种竞争性更新中，我们将完善雄激素受体（AR）， HER2受体（HER2）和热激蛋白90（HSP90）成像方法先前发明或 在ICMIC下开发。我们对这些分子成像方法的关注是基于生物学联系 在这三个分子之间，包括AR在抗性前列腺癌和临床上的关键作用 HER2，HSP90和组蛋白脱乙酰基酶（HDAC）抑制剂药物的潜力用于治疗前列腺和其他 主要癌症。在特定的目标1a中，我们将使用[18F] 16b开发一个动力学方法来定量AR castrate抗性前列腺癌中的二氢睾丸激素（FDHT），其原理将改善 治疗选择和监测靶向AR的药物。根据我们的先前发现，以特定的目的 1b，我们提出了通过添加适当的药物化学路径来改善AR放射线 侧链，延迟代谢产物形成并增加AR结合亲和力。在特定的目标2中，我们继续 基于Herceptin IgG，Fab'2和Fab'的宠物标记的抗体形式的HER2靶向开发。在 具体目标3，我们将探索Lodine-124标记为基于嘌呤的HSP90抑制剂的潜力 HSP90的代理。在特定目标4中，我们将继续优化的临床成像范例 使用FDHT，FDG，C-11 蛋氨酸和F-18 l-胸苷（FLT）。计划在前列腺癌中针对药物进行临床方案 已知可以抑制AR，HSP90和HER2分子，例如AR靶向剂，Ansamycin和 基于嘌呤的HSP90抑制剂，赫赛汀和HDAC抑制剂。总而言之，以我们先验为基础 研究，我们计划继续发现分子成像的发现，开发和翻译的过程 高级实践的方法，从而改善了人类前列腺癌的诊断和治疗。