Signal Transduction Events and the Regulation of Cell Growth

信号转导事件和细胞生长的调节

• 批准号: 8554158
• 负责人: JANE B TREPEL
• 金额: $ 88.71万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8554158
• 关键词: Agreement; Androgen Antagonists; Androgen Receptor; Androgens; Angiogenesis Inhibitors; Antineoplastic Agents; Basic Science; Binding; Biological Assay; Blood; C-terminal; Cancer Etiology; Cell Nucleus; Cessation of life; Characteristics; Chemicals; Client; Clinical; Clinical Drug Development; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cooperative Research and Development Agreement; Data; Detection; Development; Drug Delivery Systems; ERBB2 gene; Endothelial Cells; Epithelial; Event; Extramural Activities; Fingers; Gene Expression; Genetic Polymorphism; Goals; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; IgG1; Immune; Immune Targeting; Industry; Institutes; Intellectual Property; Laboratories; Legal patent; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Molecular Target; Monoclonal Antibodies; N-terminal; Neoplasm Metastasis; Neoplasms; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Phase; Phase I/II Trial; Phase II Clinical Trials; Process; Proteasome Inhibitor; Publishing; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Sampling; Second Primary Neoplasms; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Somatotropin; Staging; Stem cells; Structure-Activity Relationship; Surgeon; Synthesis Chemistry; Technology; Texas; Therapeutic antibodies; Translational Research; United States; United States National Institutes of Health; Universities; Urologic Oncology; Work; Writing; base; cancer cell; cancer therapy; cell growth regulation; deprivation; design; drug development; drug discovery; high throughput screening; hormone refractory prostate cancer; hormone therapy; improved; in vivo; inhibitor/antagonist; men; neoplastic cell; novel; novel strategies; novel therapeutic intervention; oncology; pre-clinical; receptor; research and development; response; scaffold; small molecule libraries; tacrolimus binding protein 4; therapeutic development; tumor; urologic

This project is designed to develop a new approach to cancer treatment through the study of growth, survival, and metastasis regulatory signal transduction events that identify molecular targets for anticancer drug development. Our work is divided into basic research and translational research through the Preclinical Development Research Core, a translational drug development facility that we have established. Our work is currently focused on (1) the development of novel antiandrogens targeting the Hsp90-Hsp70 supramolecular complex, and (2) development and implementation of pharmacodynamic assays for targeted therapy trials, including assays for response to antiangiogenics, histone deacetylase inhibitors, Hsp90 inhibitors, immune-targeting agents, and detection of circulating epithelial tumor cells (CTCs) pre- and post-drug therapy, and, in collaboration with Dr. Peter Pinto of the Urologic Oncology Branch, CTC assays pre- and post-surgery.(1) Prostate cancer is the most common malignancy and second leading cause of cancer-related death in men in the United States. Androgen deprivation is the mainstay of treatment for men with metastatic prostate cancer, but almost all men treated with hormonal therapy will progress to a castrate-resistant state (CRPC). Once CRPC develops, responses to second-line treatment are limited and median survival is currently approximately 12 to 18 months. Clearly a new therapeutic approach is needed for the treatment of CRPC. Once thought to reflect an androgen-independent state, it is now appreciated that CRPC is driven by androgen receptor (AR) signaling, and that more effective blockade of this pathway would be of enormous value in improving the efficacy of CRCP therapy. In the past three years we have performed high-throughput screens and structure-activity relationship analyses (SAR), and have developed several novel antiandrogens for which the NIH has filed for intellectual property protection. In the first project we worked in collaboration with a number of labs including Len Neckers of the Urologic Oncology Branch, NCI and Marc Cox of the University of Texas, El Paso. We contributed to the SAR by identifying the most potent compound, and we performed all of the AR-driven gene expression studies. This project identified the mechanism of action of the active molecule as targeting of the Hsp90-AR complex with FKBP52, by binding to the Hsp90-FKBP52 interface. As a result of this binding Hsp90 does not release AR in response to androgen binding. Thus AR does not enter the nucleus and AR signaling is inhibited. We published a report on this work in PNAS this year, and NIH filed for patent on the compound. As a result of an SAR on a different chemical library we have identified a new antiandrogen with a novel chemical scaffold and a unique mechanism of action. Compound syntheses were guided by the results of our gene expression analyses, and performed by Sanjay Malhotra and Vineet Kumar of the NCI-Frederick Laboratory of Synthetic Chemistry. My laboratory is working on elucidating the mechanism of action of compounds with this scaffold, and NIH has filed a second antiandrogen patent for these compounds. Our data thus far demonstrate that these compounds have the unique ability to cause degradation of Hsp90 clients, including AR, without binding to either the N-terminal or C-terminal of Hsp90 itself.(2) The Preclinical Development Research Core has been working with intramural, extramural and industry investigators on a range of phase I and phase II clinical trials. I am an associate investigator on 40 clinical trials. For each of these trials we work with the PI to develop novel pharmacodynamic endpoints, including analysis of circulating endothelial progenitor cells, mature endothelial cells, circulating epithelial tumors cells and a wide range of rare immune subsets. This year we have analyzed over 120 patients for these parameters. Our analysis of circulating endothelial cell subsets have shown statistically-significant correlation with clinical outcome in phase I and phase II trials. Our basic research on signal transduction pathways that can inhibit the growth of hormone-refractory prostate cancer cells led us to the identification of histone deacetylase as a critical target in this neoplasm. We have developed a novel pharmacodynamic assay for assessment of HDAC inhibitor activity in vivo. The NCI has applied for a patent on our work, which is uniquely capable of analyzing HDAC inhibitor activity in as little blood as in a finger-stick, and can look at combination therapy pharmacodynamic responses by examining 10 parameters simultaneously. We have implemented this technology in several published clinical trials (Gojo et al. Blood 109:2781-2790, 2007 and Kummar et al., Clin. Cancer Res. 13:5411-5417, 2007) and this year in a phase II trial of belinostat in thymic malignancies (J. Clin. Oncol., 29:2052-2059, 2011), in which we also published data using our pharmacodynamic assay for regulatory T cell (Treg) subsets. We have established a collaboration with Drs. Jay Bradner and Stuart Schreiber of the Broad Institute to use our technology to develop new HDAC inhibitors, and a collaboration with Dr. Michael Palladino of Nereus Pharmaceuticals to study HDAC inhibitors in combination with the novel Nereus proteasome inhibitor NPI-0052. This year we have a CRADA agreement with Syndax Pharmaceuticals to support HDAC inhibitor research in the lab. We have analyzed recent progress in HDAC as a molecular target in Current Opinion in Oncology (20:639-649, 2008) and we have reviewed progress in Hsp90 inhibitors in clinical trial in Curr Top Med Chem (9:1479-1492, 2009) and Nat Rev Cancer (10:537-549, 2011). This year we have also had a CRADA agreement with Macrogenics, Inc. for development and implementation of pharmacodynamic assays for the assessment of their Fcgamma receptor-optimized anti-HER2 therapeutic antibody MGAH22. The assays we have developed and implemented include molecular assessment of Fcgamma receptor polymorphisms conferring enhanced binding of IgG1 monoclonal antibodies. Working with surgeons in the Urologic Oncology Branch we have developed assays for rare immune subsets inflitrating the tumor microenvironment, and will be employing these assays in upcoming clinical trials in urologic malignancies where they have been written in as exploratory endpoints. We have been working intensively on development of a new platform for detection of circulating epithelial tumor cells, and we are currently implementing this endpoint in twelve open clinical trials.

该项目旨在通过研究生长、生存和转移调节信号转导事件，确定抗癌药物开发的分子靶点，开发一种新的癌症治疗方法。我们的工作分为基础研究和转化研究，通过临床前开发研究核心，我们已经建立了一个转化药物开发设施。我们的工作目前集中在(1)开发针对Hsp90- hsp70超分子复合物的新型抗雄激素，(2)开发和实施靶向治疗试验的药效学分析，包括抗血管生成、组蛋白去乙酰化酶抑制剂、Hsp90抑制剂、免疫靶向药物的反应分析，以及药物治疗前后循环上皮肿瘤细胞（CTCs）的检测。CTC与泌尿外科肿瘤科的Peter Pinto医生合作，对术前和术后进行检测。(1)前列腺癌是最常见的恶性肿瘤，也是美国男性癌症相关死亡的第二大原因。雄激素剥夺是男性转移性前列腺癌的主要治疗方法，但几乎所有接受激素治疗的男性都会发展为去势抵抗状态（CRPC）。一旦发生CRPC，对二线治疗的反应是有限的，目前中位生存期约为12至18个月。显然，需要一种新的治疗方法来治疗CRPC。曾被认为是雄激素不依赖状态，现在认识到CRPC是由雄激素受体（AR）信号驱动的，更有效地阻断这一途径将对提高CRCP治疗的疗效具有巨大价值。在过去的三年中，我们进行了高通量筛选和结构-活性关系分析（SAR），并开发了几种新型抗雄激素，这些抗雄激素已被NIH申请知识产权保护。在第一个项目中，我们与许多实验室合作，包括美国国家癌症研究所泌尿肿瘤科的Len Neckers和德克萨斯大学埃尔帕索分校的Marc Cox。我们通过识别最有效的化合物来贡献SAR，我们进行了所有ar驱动的基因表达研究。本项目通过结合Hsp90-FKBP52界面，确定了该活性分子的作用机制为靶向Hsp90-AR复合物与FKBP52。由于这种结合，Hsp90在雄激素结合时不会释放AR。因此AR不能进入细胞核，AR信号被抑制。我们今年在《美国国家科学院院刊》上发表了一篇关于这项工作的报告，美国国立卫生研究院也为这种化合物申请了专利。由于对不同化学文库的SAR，我们已经确定了一种新的抗雄激素，具有新的化学支架和独特的作用机制。化合物的合成以我们的基因表达分析结果为指导，由NCI-Frederick合成化学实验室的Sanjay Malhotra和Vineet Kumar进行。我的实验室正致力于阐明这种支架化合物的作用机制，美国国立卫生研究院已经为这些化合物申请了第二个抗雄激素专利。到目前为止，我们的数据表明，这些化合物具有独特的能力，可以导致Hsp90客户端（包括AR）的降解，而不与Hsp90本身的n端或c端结合。(2)临床前开发研究核心一直在与校内、校外和行业研究人员合作进行一系列I期和II期临床试验。我是40项临床试验的副研究员。对于每一项试验，我们都与PI合作开发新的药效学终点，包括循环内皮祖细胞、成熟内皮细胞、循环上皮肿瘤细胞和广泛的罕见免疫亚群的分析。今年我们分析了120多名患者的这些参数。我们对循环内皮细胞亚群的分析显示，在I期和II期试验中，与临床结果有统计学意义的相关性。我们对抑制激素难治性前列腺癌细胞生长的信号转导通路的基础研究使我们确定组蛋白去乙酰化酶是该肿瘤的关键靶点。我们开发了一种新的药效学方法来评估体内HDAC抑制剂的活性。NCI已经为我们的工作申请了专利，这项工作具有独特的能力，可以分析HDAC抑制剂在手指棒一样少的血液中的活性，并且可以通过同时检查10个参数来观察联合治疗的药效学反应。我们已经在几个已发表的临床试验中实施了这项技术（Gojo等人）。《中华医学杂志》，2007年第9期。Cancer Res. 13:5411-5417, 2007)和今年belinostat治疗胸腺恶性肿瘤的II期临床试验(J. clint。肿瘤防治杂志。（29:2052-2059, 2011），其中我们还发表了使用我们的调节性T细胞（Treg）亚群药效学分析的数据。我们已经和dr。布罗德研究所的Jay Bradner和Stuart Schreiber使用我们的技术开发新的HDAC抑制剂，并与Nereus制药公司的Michael Palladino博士合作研究HDAC抑制剂与新型Nereus蛋白酶体抑制剂NPI-0052的联合使用。今年，我们与Syndax制药公司达成了CRADA协议，以支持实验室中的HDAC抑制剂研究。我们在Current Opinion in Oncology（20:639-649, 2008）中分析了HDAC作为分子靶点的最新进展，我们在Curr Top Med Chem（9:1479-1492, 2009）和Nat Rev Cancer（10:53 37-549, 2011）中回顾了Hsp90抑制剂在临床试验中的进展。今年，我们还与Macrogenics， Inc.达成了CRADA协议，开发和实施药效学分析，以评估其Fcgamma受体优化的抗her2治疗性抗体MGAH22。我们开发和实施的检测方法包括fgamma受体多态性的分子评估，从而增强IgG1单克隆抗体的结合。与泌尿外科肿瘤科的外科医生合作，我们开发了罕见免疫亚群浸润肿瘤微环境的检测方法，并将在即将进行的泌尿系统恶性肿瘤临床试验中使用这些检测方法，这些检测方法已被作为探索性终点写入。我们一直致力于开发一种检测循环上皮肿瘤细胞的新平台，目前我们正在12项开放式临床试验中实施这一终点。