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

• 批准号: 7944051
• 负责人: PHILLIP G FEBBO
• 金额: $ 49.69万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944051
• 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

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（由应用程序提供）：此应用程序地址挑战区域（15）转化科学和特定的高优先挑战主题15-CA-102*理解骑马难治性癌的机制用于治疗靶向。雄激素，雄激素受体（AR）和AR信号途径与前列腺癌发生密切相关。抑制AR介导的信号当前是治疗转移性疾病的最有效方法。然而，尽管有实质性的临床反应，但针对前列腺癌的雄激素剥夺疗法（ADT）很少导致持久的缓解或治疗方法。大多数癌症发展为临床状态，称为D3期，雄激素独立或难治性。但是，大量的临床和实验室数据表明，这些后来的术语实际上是错误的名称。为了清晰和简单，这种临床状态认识到癌症进展的机制很复杂，因此将其准确地归类为cast割前列腺癌（CRPC）。该术语允许包含已知和假设的过程，这些过程允许在雄激素耗尽的环境中前列腺癌的生长。导致CPRC的分子事件仍然是一个活跃的研究领域，它代表了旨在降低前列腺癌的发病率和死亡率的疗法的焦点。这些研究的一个关键起点是观察到的观察结果，即CRPC的绝大多数（但不是全部）继续存在，以暴露于强大的雄激素调节的细胞过程（例如PSA合成/分泌），表明AR信号传导维持或重新构成。这一发现促使人们搜索了导致castrate环境中持续AR激活的机制。尽管当前的焦点适当地集中在AR和ARPATH作为理解和治疗CRPC的焦点上，但对于该领域来说，一旦干预措施有效地消融AR信号传导，该领域重要的是预期将运行的治疗抗性机制。我们的初步研究涉及一系列CRPC转移酶，表明在AR作用水平中存在显着的异质性：某些CRPC肿瘤暴露于稳健的AR信号等于局部的NA¿VE前列腺癌，而其他CRPC肿瘤则具有微不足道或没有AR活性（有效地“ AR-NULL”）。重要的是，即使在表现出持续的AR信号传导的肿瘤患者中，也存在不经常活性或有限的AR活性的肿瘤沉积物。在过去的几年中，我们组装的数据支持CRPC分解为两个广泛的表型类别（每个具有多种亚型），在AR信号的放大器上，在aR信号的放大器上进行了定义：具有AR活性（AR-ON）的肿瘤（AR-ON）和具有降低或无AR活性的肿瘤（AR-OFF）。尽管个体可能患有疾病，其中一种表型占另一个表型，但大多数患者会有一些表现出两种表型的肿瘤。我们预计，通过确定与每种CRPC表型相关的关键分子途径（AR-ON V AR）以及协调针对CRPC男性持续细胞存活的那些不同的途径，将导致前列腺癌预后的显着改善。目前，目前尚不清楚哪些表型，基因型和随之而来的显性生长和生存途径将在AR-ON或AR-OFF CRPC中运行。该研究建议的目的是定义，类别和靶标，即允许在AR-ON和AR-OFF CRPC中进行前列腺癌存活/增殖的主要细胞途径。实现这一目标，提出了两个具体的目标：AIM 1将将基于生物信息学的方法与基因表达测量值进行定量测量，以定义与CRPC的AR-ON和AR-OFF状态相关的途径； AIM 2将确定与AR-ON和AR-OFF CRPC相关的靶向/抑制途径是否会限制抑制castration的耐肿瘤生长。该研究提案的关键属性集中在人类生物测量的直接评估中，以评估CRPC多样性。为了有效地实现我们的目标，我们组建了来自3个学术中心的专家，​​这些专家专门研究了高级前列腺癌研究的广泛基础科学和临床研究计划。这些中心在前列腺癌症护理和研究方面具有悠久的传统，并为其当地经济和创造经济增长的发现做出了广泛的贡献。当前的提案将通过在西雅图和达勒姆及其合作机构创造或留住5个就业机会来对经济产生积极影响。 （根据生物医学行业的说法，对于生物医学组织的每一名员工，将在该行业的服务公司中雇用另外三到五名。）我们正在寻求这项挑战，以快速实施我们的研究策略，目的是开发能够将特定特定疗法引导到这些患者最有可能获得益处的新型分层生物标志物。所有研究发现和数据都将通过特定于项目的网站向研究社区提供给研究社区。 公共卫生相关性：在马酮（雄激素）抑制后进展的晚期转移性前列腺癌，尚无已知治愈方法，并有助于实质性的发病率和死亡率。该提案旨在使用基因表达的全面测量来将抗性castration抗性前列腺癌分类为离散的分子亚型，并定义那些有助于持续肿瘤存活和生长的生化途径。分子定义的生存途径的相关性将在临床前模型中进行评估，并且有望的靶标将被提高并优先考虑人类临床试验的发展。该项目将产生新的概念，并为包括生物信息学在内的高级生物医学研究的培训提供新的工作。该项目还通过确定需要通过制药行业发展的前列腺癌的新疗法来实现进一步的经济发展。