Targeting Cell Cycle Alterations to Improve Treatment for Advanced Prostate Cancer

针对细胞周期改变改善晚期前列腺癌的治疗

• 批准号: 9343456
• 负责人: KAREN E KNUDSEN
• 金额: $ 36.74万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9343456
• 关键词: Androgen Receptor; Androgen Suppression; Binding; Biological Markers; Biopsy; Bypass; CDK4 gene; Castration; Cell Cycle; Cell Cycle Regulation; Cells; Chromatin; Clinical; Clinical Data; Clinical Management; Clinical Trials; Collaborations; Complement; Complex; Cyclin D1; Cyclin-Dependent Kinases; Cytostatics; Data; Dependence; Development; Disease; Disease Progression; Disease Resistance; Disease model; Disease stratification; Failure; Funding; Gene Expression; Goals; Growth; Hypersensitivity; Intervention; Investigation; Laboratories; Link; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Profiling; Pathway interactions; Patient-Focused Outcomes; Patients; Phase I/II Trial; Phenotype; Phosphorylation; Play; Predisposition; Production; Recurrence; Regimen; Resistance; Role; Specificity; Stratification; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Treatment Protocols; Treatment outcome; Up-Regulation; actionable mutation; advanced disease; base; cancer therapy; castration resistant prostate cancer; cytotoxic; effective therapy; experimental study; gain of function; hormone therapy; human disease; improved; inhibitor/antagonist; neoplastic cell; novel; outcome prediction; personalized medicine; pre-clinical; precision medicine; prevent; prostate cancer cell; receptor; receptor expression; resistance mechanism; response; response biomarker; targeted cancer therapy; targeted treatment; therapeutic development; therapy outcome; treatment response; treatment stratification; tumor; tumor progression

Abstract Recent advances in understanding progression to castration-resistant prostate cancer (CRPC) has led to development of therapeutics that slightly increase overall survival; however, the majority of patients with CRPC succumb to disease within 2-3 years, indicating the need for metrics of precision medicine, and development of additional therapeutics. Here, we propose an ambitious approach to stratify and enhance treatment for metastatic CRPC to improve therapeutic outcomes, based on cell cycle alterations that we recently discovered. The studies described will explore untouched territory with regard to PCa targeted therapy based management, and will provide the first assessment of treatment based on subtyping in this disease context. Moreover, the studies described could provide the first biomarker with which to stratify prostate cancer treatment, and to improve therapy for patients with advanced disease. Our collective findings strongly suggest that alterations in the RB-cyclin D1/CDK4 axis play major roles in disease progression, and molecular investigation of these alterations provide a rational basis for disease stratification and improved management of advanced PCa. This postulate will be challenged in carefully planned specific aim. First, building on 2 funded clinical trials, we will use biopsy material, novel models of disease, and co-clinical trials to challenge the hypothesis that the RB-cyclin D1/CDK4 axis can be developed as biomarkers of response and as metrics for treatment stratification (Aim 1). These studies have the potential for near-term patient benefit, and could identify the first biomarker for personalized medicine in advanced PCa. Second, robust models will be used to interrogate the molecular basis of responsiveness to therapeutic directed toward alterations in RB and/or cyclin D1 status (Aim 2). Studies planned will provide critical information as to specificity and clinical placement of RB and cyclin D1- alteration dependent interventions. Finally, targeting the Rb-cyclin D1/CDK4 axis forces reliance of tumor cells on G2/M cyclin dependent kinases—plans were thereby developed to leverage this cell cycle dependence, with a goal toward discovery of new means to maximize efficacy of treatment for cells with RB-cyclin D1/CDK4 alterations (Aim 3). These collective aims build off the unique collaboration amongst a leader in clinical management of advanced PCa and a pioneer of novel clinical trials (Dr. Kelly), and a leading AR biologist with significant expertise in studying cell cycle regulation and PCa-associated cell cycle alterations (Dr. Knudsen), and an expert in clinical targeting of cell cycle alterations (Dr. O’Dwyer). As proposed, this project has the capacity to illuminate the means by which perturbations Rb-cyclin D1 alterations alter disease progression and therapeutic response in human disease, and to dramatically alter PCa management.

摘要 最近在了解去势抵抗性前列腺癌（CRPC）进展方面的进展导致 治疗的发展，略有增加总生存期;然而，大多数患者 CRPC在2-3年内死于疾病，表明需要精确医学的指标， 开发新的治疗方法。在这里，我们提出了一种雄心勃勃的分层和增强方法 转移性CRPC的治疗，以改善治疗结果，基于细胞周期的改变，我们 最近发现的。所述研究将探索与PCa目标相关的未触及领域 治疗为基础的管理，并将提供第一次评估的治疗基础上亚型在这一点上， 疾病背景。此外，所描述的研究可以提供用于分层的第一个生物标志物。 前列腺癌治疗，并改善晚期疾病患者的治疗。我们的集体 研究结果强烈提示RB-细胞周期蛋白D1/CDK 4轴的改变在疾病中起主要作用， 这些变化的分子研究为疾病的进展提供了合理的基础。 分层和改善晚期PCa的管理。这一假设将受到挑战， 精心策划的具体目标。首先，在2个资助的临床试验的基础上，我们将使用活检材料， 疾病模型，以及共同临床试验，以挑战RB-细胞周期蛋白D1/CDK 4轴可以被 作为反应的生物标志物和治疗分层的指标（目标1）。这些研究 具有近期患者受益的潜力，并且可以确定个性化治疗的第一个生物标志物。 晚期前列腺癌的药物治疗其次，将使用稳健的模型来询问 针对RB和/或细胞周期蛋白D1状态改变的治疗反应性（目的2）。研究 计划将提供关于RB和细胞周期蛋白D1的特异性和临床定位的关键信息- 改变依赖性干预。最后，靶向Rb-细胞周期蛋白D1/CDK 4轴迫使肿瘤依赖性 G2/M细胞周期蛋白依赖性激酶-计划的细胞，从而开发利用这种细胞周期 依赖性，目标是发现新的方法，以最大限度地提高对具有 RB-细胞周期蛋白D1/CDK 4改变（Aim 3）。这些集体目标建立在一个人之间独特的合作之上 晚期PCa临床管理的领导者和新型临床试验的先驱（Kelly博士），以及 在研究细胞周期调控和PCA相关细胞周期方面具有重要专业知识的领先AR生物学家 他是细胞周期改变的临床靶向专家（Dr. Knudsen）和细胞周期改变的临床靶向专家（Dr. O 'Dwyer）。作为 建议，该项目有能力照亮的手段，扰动Rb-细胞周期蛋白D1 改变改变人类疾病的疾病进展和治疗反应， 显著改变PCa管理。