Mechanism-based Classification and Targeting of Castration-Resistant Prostate Can

去势抵抗性前列腺癌的基于机制的分类和靶向治疗

基本信息

批准号：
7837290
负责人：
PHILLIP G FEBBO
金额：
$ 50万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837290
关键词：
Address Adrenal Glands Androgen Antagonists Androgen Receptor Androgen Suppression Androgen Therapy Androgens Area Automobile Driving Basic Science Biochemical Pathway Bioinformatics Biological Markers Biomedical Research Bypass Castration Categories Cell Survival Cell physiology Cells Classification Clinical Clinical Research Clinical Trials Communities Complex Data Dependence Deposition Development Disease Disease remission Drug Industry Economic Development Economics Employee Environment Enzymes Evaluation Event Exhibits Gene Expression Genes Genome Genomics Genotype Goals Grant Growth Heterogeneity Hormones Human Human Development Individual Industry Infrequent Neoplasm Institution Intervention Investigation Laboratories Ligands Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Metabolic Pathway Metastatic Prostate Cancer Molecular Morbidity - disease rate Neoplasm Metastasis New Agents Occupations Oncogenes Oncogenic Outcome Pathway interactions Patients Phenotype Pre-Clinical Model Process Prostate Prostate Cancer therapy Prostate-Specific Antigen Receptor Activation Receptor Signaling Refractory Regulatory Pathway Research Research Proposals Resistance Serum Services Signal Pathway Signal Transduction Staging Stanolone Stratification Stream TMPRSS2 gene Tars Testing Testosterone Therapeutic Time Training Translational Research Work base cancer care cancer cell carcinogenesis deprivation effective therapy improved inhibitor/antagonist lifetime risk male men mortality novel pre-clinical programs prostate carcinogenesis public health relevance receptor expression receptor function receptor-mediated signaling reconstitution resistance mechanism response segregation stem therapeutic target therapy design tumor tumor growth tumor progression web site

项目摘要

DESCRIPTION (provided by applicant): This application addresses the Challenge Area (15) Translational Science and specific high priority Challenge Topic 15-CA-102* Understanding mechanisms of hormone refractory cancers for therapeutic targeting. Androgens, the Androgen Receptor (AR) and the AR-signaling pathway are intimately associated with prostate carcinogenesis. Suppressing AR-mediated signaling currently represents the most effective approach for treating metastatic disease. However, despite substantial clinical responses, androgen deprivation therapy (ADT) for metastatic prostate cancer rarely results in durable remissions or cures. Most cancers progress to a clinical state synonymously termed Stage D3, androgen-independent, or hormone-refractory. However, substantial clinical and laboratory data indicate that these latter terms are actually misnomers. Recognizing that the mechanisms underlying cancer progression are complex, for clarity and simplicity this clinical state is more accurately classified as Castration Resistant Prostate Cancer (CRPC). This term allows for inclusion of known and hypothesized processes that allow for prostate cancer growth in an androgen-depleted environment. The molecular events leading to CPRC remain an active area of investigation and represent a focal point for therapies designed to reduce the morbidity and mortality attributed to prostate cancer. A key starting point for these studies centers on the observation that the vast majority (but not all) of CRPC continue to exhibit robust androgen-regulated cellular processes (e.g. PSA synthesis/secretion), indicating that AR signaling is maintained or reconstituted. This finding has prompted a search for mechanisms that contribute to continued AR activation in the castrate environment. While the current focus appropriately centers on AR and the ARpathway as the focal point for understanding and treating CRPC, it is important for the field to anticipate therapy- resistance mechanisms that will be operative once interventions have effectively ablated AR signaling. Our preliminary studies involving a spectrum of CRPC metastases have demonstrated that significant heterogeneity exists in the level of AR action: some CRPC tumors exhibit robust AR signaling equal to that of localized, hormone na¿ve prostate cancers and others have trivial or no AR activity (effectively "AR-null"). Importantly, even in patients with tumors that demonstrate persistent AR signaling, there are infrequent tumor deposits with no or limited AR activity. The data we have assembled over the past several years supports the segregation of CRPC into two broad phenotypic categories---each with multiple subtypes---initially defined with respect to amplitude of AR signaling: tumors with preserved AR activity (AR-ON) and those with diminished or no AR activity (AR-OFF). While individuals are likely to have disease in which one phenotype predominates over the other, most patients will have some tumors exhibiting both phenotypes. We anticipate that significant improvements in prostate cancer outcomes will result from identifying the key molecular pathways associated with each CRPC phenotype (AR-ON v AR-OFF) and coordinately targeting those distinct pathways responsible for continued cell survival in men with CRPC. At this time, it is unclear what phenotypes, genotypes, and attendant dominant growth and survival pathways will be operative in either AR-ON or AR-OFF CRPC. The goal of this research proposal is to define, categorize, and target, the dominant cellular pathways that allow for prostate cancer survival/proliferation in AR-ON and AR-OFF CRPC. To accomplish this goal, two Specific Aims are proposed: Aim 1 will integrate genome-scale bioinformatics-based approaches with quantitative measurements of gene expression measurements to define the pathways associated with AR-on and AR-off states of CRPC; Aim 2 will determine if targeting/inhibiting the pathway(s) associated with AR-on and AR-off CRPC will restrain castration resistant tumor growth. A key attribute of this research proposal centers on the direct evaluation of human biospecimens for the evaluation of CRPC diversity. To efficiently carry out our objectives, we have assembled experts from 3 academic centers with extensive basic science and clinical research programs devoted to the study of advanced prostate cancer. These centers have long traditions of excellence in prostate cancer care and research and have contributed broadly to their local economies and in discoveries that have created economic growth. The current proposal would positively impact the economy by creating or retaining 5 jobs in Seattle and Durham and their collaborating institutions. (According to the Biomedical Industry, for every one employee of a biomedical organization, another three to five will be employed in firms that service that industry.) We are seeking this Challenge Grant to rapidly implement our research strategy with the goal of developing novel stratification biomarkers capable of directing specific therapies to those patients most likely to derive benefit. All research findings and data will be made available to the research community through a freely-accessible project-specific website. PUBLIC HEALTH RELEVANCE: Advanced, metastatic prostate cancer that progresses following hormone (androgen) suppression, has no known cure, and contributes to substantial morbidity and mortality. This proposal aims to categorize advanced castration-resistant prostate cancers into discrete molecular subtypes using comprehensive measures of gene expression, and define those biochemical pathways that contribute to continued tumor survival and growth. The relevance of molecularly-defined survival pathways will be assessed in preclinical models, and promising targets will be advanced and prioritized for the development of human clinical trials. The project will generate new concepts and provide new jobs with training in advanced biomedical research including bioinformatics. The project also has the potential for further economic development by identifying new therapies for prostate cancer that will require advancement through the pharmaceutical industry.

描述（由申请人提供）：本申请涉及挑战领域 (15) 转化科学和特定的高优先级挑战主题 15-CA-102* 了解激素难治性癌症的治疗靶向机制。 AR 信号通路与前列腺癌密切相关，目前抑制 AR 介导的信号通路是治疗转移性疾病的最有效方法。转移性前列腺癌的雄激素剥夺疗法 (ADT) 很少会导致持久缓解或治愈，大多数癌症会进展至 D3 期、雄激素非依赖性或激素难治性的临床状态。然而，大量的临床和实验室数据表明，后者。认识到癌症进展的机制很复杂，为了清楚和简单起见，这种临床状态更准确地归类为去势抵抗性前列腺癌（CRPC）。纳入已知的和开创性的过程，允许前列腺癌在雄激素耗尽的环境中生长，导致 CPRC 的分子事件仍然是一个活跃的研究领域，也是旨在降低前列腺发病率和死亡率的治疗的焦点。这些研究的一个关键出发点是观察到绝大多数（但不是全部）CRPC 继续表现出强大的雄激素调节细胞过程（例如 PSA 合成/分泌），表明 AR 信号传导得以维持或重建。这一发现寻找了在阉割环境中促进 AR 持续激活的机制，虽然当前的焦点适当地集中在 AR 和 AR 通路上，作为理解和治疗 CRPC 的焦点，但该领域预测治疗非常重要。一旦干预措施有效消除 AR 信号传导，我们的初步研究表明，AR 作用水平存在显着的异质性：一些 CRPC 肿瘤表现出与局部激素相同的强大 AR 信号传导。呐5种癌症和其他癌症具有微不足道的AR活性（实际上是“AR无效”），即使在具有持续AR信号传导的肿瘤患者中，也很少有前列腺AR活性不存在或有限的肿瘤沉积物。过去几年的研究支持将 CRPC 分为两大表型类别（每个类别都有多个亚型），最初根据 AR 信号传导的幅度进行定义：保留 AR 活性的肿瘤（AR-ON）和 AR 活性减弱或减弱的肿瘤。不AR 活性 (AR-OFF)。虽然个体可能患有一种表型占主导地位的疾病，但大多数患者的一些肿瘤会表现出两种表型，我们预计，通过识别关键分子，前列腺癌的结果将得到显着改善。与每种 CRPC 表型 (AR-ON v AR-OFF) 相关的途径，并协调针对那些负责 CRPC 男性持续细胞存活的不同途径。目前，尚不清楚哪些表型、基因型以及伴随的显性生长和存活途径。将在任一情况下运行AR-ON 或 AR-OFF CRPC。本研究提案的目标是定义、分类和靶向允许 AR-ON 和 AR-OFF CRPC 中前列腺癌存活/增殖的主要细胞途径。提出了两个具体目标：目标 1 将基于基因组规模的生物信息学方法与基因表达测量的定量测量相结合，以定义与 CRPC 的 AR-on 和 AR-off 状态相关的途径；目标 2 将确定是否靶向/抑制；这与 AR-on 和 AR-off CRPC 相关的途径将抑制去势抵抗性肿瘤的生长，该研究提案的一个关键属性是直接评估人类生物样本以评估 CRPC 的多样性。我们聚集了来自 3 个学术中心的专家，这些中心拥有广泛的基础科学和临床研究项目，致力于晚期前列腺癌的研究，这些中心在前列腺癌护理和研究方面拥有悠久的卓越传统，并为当地经济和发现做出了广泛贡献。目前的提案将创造经济增长。通过在西雅图和达勒姆及其合作机构创造或保留 5 个就业岗位，对经济产生积极影响（根据生物医学行业的数据，生物医学组织每增加一名员工，就会有另外三到五名员工受雇于为该行业提供服务的公司。）我们正在寻求这项挑战拨款，以快速实施我们的研究战略，目标是开发能够为最有可能受益的患者提供特定治疗的新型分层生物标志物。所有研究结果和数据都将通过免费方式向研究界提供。 - 无障碍项目特定网站。公共健康相关性：晚期转移性前列腺癌在激素（雄激素）抑制后进展，目前尚无已知的治愈方法，并导致大量的发病率和死亡率。该提案旨在利用综合措施将晚期去势抵抗性前列腺癌分类为离散的分子亚型。基因表达，并定义那些有助于肿瘤持续生存和生长的生化途径。将在临床前模型中评估分子定义的生存途径的相关性，并将推进有希望的目标并优先考虑开发。该项目将产生新概念，并提供新的就业机会，并提供包括生物信息学在内的先进生物医学研究培训。该项目还具有通过确定需要通过制药行业进步的前列腺癌新疗法来进一步发展经济的潜力。