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Signal Transduction Events and the Regulation of Cell Growth

信号转导事件和细胞生长的调节

基本信息

批准号：
9154362
负责人：
JANE B TREPEL
金额：
$ 84.67万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/9154362
关键词：
Agreement Androgen Antagonists Androgen Receptor Androgens Angiogenesis Inhibitors Antineoplastic Agents Basic Science Binding Biological Assay Biological Markers Blood C-terminal Cancer Etiology Cell Nucleus Cells 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 Targeting ERBB2 gene Endothelial Cells Epithelial Event Exemestane Extramural Activities Fc Receptor Fingers Gene Expression Genetic Polymorphism Genitourinary system Goals Growth Histone Deacetylase Histone Deacetylase Inhibitor IgG1 Immune Immune Targeting Industry Institutes Intellectual Property Laboratories Legal patent Ligand Binding Domain Malignant Neoplasms Malignant neoplasm of prostate Medical Oncologist Metastatic Prostate Cancer Molecular Molecular Target Monoclonal Antibodies N-terminal Neoplasm Circulating Cells Neoplasm Metastasis Neoplasms Non-Steroidal Aromatase Inhibitor Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacotherapy Phase Phase I/II Trial Phase III Clinical Trials Postmenopause Process Proteasome Inhibitor Publishing RNA Splicing Radiation therapy Randomized Receptor Signaling Recurrence Regulatory T-Lymphocyte Reporting Research Research Personnel Resistance Sampling Second Primary Neoplasms Series Signal Pathway Signal Transduction Signal Transduction Pathway Somatotropin Staging Stem cells Structure-Activity Relationship Surgeon Synthesis Chemistry Technology Testing Texas Therapeutic antibodies Therapy trial Translational Research United States United States National Institutes of Health Universities Urologic Oncology Vaccines Variant Woman Work anticancer research base cancer therapy cell growth regulation cytotoxic deprivation design drug development drug discovery high risk high throughput screening hormone refractory prostate cancer hormone therapy improved in vivo inhibitor/antagonist malignant breast neoplasm men mutant neoplastic cell novel novel strategies novel therapeutic intervention oncology phase 2 study phase II trial phase III trial pre-clinical prostate cancer cell receptor receptor expression response scaffold small molecule libraries tacrolimus binding protein 4 targeted treatment therapeutic development tumor microenvironment

项目摘要

This project is designed to develop new approaches 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 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 most men treated with hormonal therapy will progress to a castrate-resistant state (CRPC). Once CRPC develops, treatment options are limited and median overall survival is currently approximately 32 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. 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 the Hsp90-AR-FKBP52 complex 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 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. These compounds have the ability to cause degradation of AR splice variants characteristic of CRPC and are cytotoxic to CRPC cells driven by ligand binding domain (LBD) mutant AR and splice variant AR. In addition, we performed SAR studies on a novel series of dihydropyridones and identified an antiandrogen with potency comparable to enzalutamide (J Med Chem 56:8280-8297, 2014). (2) The Preclinical Development Core has been working with intramural, extramural and industry investigators on a range of phase I, phase II and phase III clinical trials. I am an Associate Investigator on 50 clinical trials either open to accrual or open for analysis this year. 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 tumor cells (CTCs) and a wide range of rare immune subsets, as well as various molecular analyses. This year we have analyzed over 300 patients for these parameters. Our analyses of circulating endothelial cell subsets, circulating tumor cells and rare immune subsets including analysis of immune checkpoint receptor expression 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, Kummar et al., Clin. Cancer Res. 13:5411-5417, 2007), 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, and in a randomized phase II trial of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor (J. Clin. Oncol. 31:228-2135, 2013). This year this assay is being tested as a predictive biomarker of HDAC inhibitor plus exemestane response in a randomized phase III trial of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. 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 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), Nat Rev Cancer (10:537-549, 2011) and Clinical Cancer Research (20:275-277, 2014). This year we have also had a CRADA agreement with Macrogenics, Inc. for development and implementation of pharmacodynamic assays for the assessment of their Fc 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 and medical oncologists in the Genitourinary Malignancies Branch we have developed assays for rare immune subsets infiltrating the tumor microenvironment, and we are employing these assays in a clinical trial in a randomized phase II study of androgen deprivation therapy and radiation therapy with or without Stimuvax vaccine in high-risk prostate cancer. We have been working intensively on development of a new platform for detection of circulating epithelial tumor cells (CTCs), and we are currently implementing this endpoint in 24 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来开发新的癌症治疗方法，从而确定抗癌药物开发的分子靶点。我们的工作分为基础研究和通过临床前开发核心（我们建立的转化药物开发设施）进行的转化研究。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，但大多数接受激素治疗的男性会发展为去势抵抗状态（CRPC）。一旦发生CRPC，治疗选择有限，目前中位总生存期约为32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。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。本项目确定活性分子的作用机制是通过结合Hsp90-AR-FKBP52界面靶向Hsp90-AR-FKBP52复合物。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。我们在PNAS上发表了一篇关于这项工作的报告，并为该化合物申请了专利。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。这些化合物具有降解CRPC特征的AR剪接变体的能力，并且对由配体结合域（LBD）突变AR和剪接变体AR驱动的CRPC细胞具有细胞毒性。此外，我们对一系列新的二氢吡啶酮进行了SAR研究，并鉴定了一种与enzalutamide药效相当的抗雄性激素（J Med Chem 56:8280-8297, 2014）。(2)临床前开发核心一直在与校内、校外和行业研究人员合作，进行一系列I、II和III期临床试验。今年我是50项临床试验的副研究员，这些试验要么是应计的，要么是可供分析的。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（ctc）和广泛的罕见免疫亚群的分析，以及各种分子分析。今年我们分析了300多名患者的这些参数。我们对循环内皮细胞亚群、循环肿瘤细胞和罕见免疫亚群的分析，包括免疫检查点受体表达的分析，显示了与I期和II期临床结果的统计学显著相关性。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，2007,39(2):391 - 391。belinostat治疗胸腺恶性肿瘤的II期临床研究[j]。肿瘤防治杂志。， 29:2052-2059, 2011)，我们还发表了使用我们的调节性T细胞（Treg）亚群药理学分析的数据，以及在一项随机II期试验中，依西美坦加或不加恩替诺他治疗绝经后局部复发或转移性er阳性乳腺癌的妇女，使用非甾体芳香化酶抑制剂治疗（J. Clin）。中国生物医学工程学报，2013)。今年，在一项随机III期试验中，该检测作为HDAC抑制剂加依西美坦反应的预测性生物标志物，在接受非甾体芳香化酶抑制剂治疗的绝经后局部复发或转移性er阳性乳腺癌妇女中进行了依西美坦加或不加恩替诺他的试验。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）上分析了HDAC作为分子靶点的进展，并在Curr Top Med Chem（9:1479-1492, 2009）、Nat Rev Cancer（10:537-549, 2011）和clinical Cancer Research（20:275-277, 2014）上回顾了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Fc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和泌尿生殖系统恶性肿瘤科的内科肿瘤学家合作，我们开发了浸润肿瘤微环境的罕见免疫亚群的检测方法，我们正在一项随机II期研究中使用这些检测方法，该研究针对高风险前列腺癌进行雄激素剥夺治疗和放疗，有或没有Stimuvax疫苗。我们一直致力于开发一种检测循环上皮肿瘤细胞（ctc）的新平台，目前我们正在24项临床试验中实施这一终点。