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: 10212337
• 负责人: William K. Kelly
• 金额: $ 35.74万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212337
• 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; Prostate Cancer therapy; Recurrence; Regimen; Resistance; Role; Specificity; Stratification; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Treatment Protocols; Treatment outcome; Up-Regulation; advanced disease; advanced prostate cancer; base; castration resistant prostate cancer; co-clinical trial; cytotoxic; driver mutation; 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; prostate cancer progression; receptor; receptor expression; resistance mechanism; response; response biomarker; targeted cancer therapy; targeted treatment; therapeutic development; therapy outcome; treatment response; treatment stratification; tumor

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 对耐去势前列腺癌(CRPC)进展的了解最近的进展导致了 略微提高总体存活率的治疗方法的发展；然而，大多数患有 CRPC在2-3年内死于疾病，这表明需要精准医学的指标，以及 开发额外的治疗方法。在这里，我们提出了一种雄心勃勃的方法来分层和增强 治疗转移性CRPC以改善治疗结果，基于我们对细胞周期的改变 最近发现的。所描述的研究将探索与有针对性的PCA相关的未触及的领域 基于治疗的管理，并将在此提供基于亚型的第一次治疗评估 疾病背景。此外，所描述的研究可以提供第一个用于分层的生物标志物。 前列腺癌的治疗，以及提高晚期疾病患者的治疗水平。我们的集体 研究结果有力地表明，RB-Cyclin D1/CDK4轴的改变在疾病中起主要作用 进展和对这些改变的分子研究为疾病提供了合理的基础 高级PCA的分层和改进管理。这一假设将在#年受到挑战 精心策划的具体目标。首先，在两个资助的临床试验的基础上，我们将使用活检材料，新的 疾病模型和联合临床试验，挑战RB-Cyclin D1/CDK4轴可以是 被开发为反应的生物标志物和治疗分层的衡量标准(目标1)。这些研究 有可能在短期内为患者带来好处，并可以确定第一个个性化的生物标志物 高级PCA中的医学。其次，稳健的模型将被用来询问分子基础 针对Rb和/或细胞周期蛋白D1状态改变的治疗反应(目标2)。研究 计划将提供有关RB和细胞周期蛋白D1的特异性和临床定位的关键信息- 依赖变更的干预措施。最后，靶向RB-Cyclin D1/CDK4轴加强了肿瘤的依赖性 细胞在G2/M期细胞周期蛋白依赖的激酶-计划因此被开发来利用这一细胞周期 依赖，目标是发现新的方法，以最大限度地提高治疗细胞的疗效 Rb-细胞周期蛋白D1/CDK4改变(目标3)。这些集体目标建立在 高级PCA临床管理的领导者和新临床试验的先驱(Kelly博士)，以及 领先的AR生物学家，在研究细胞周期调节和PCA相关细胞周期方面拥有丰富的专业知识 他是细胞周期改变的临床靶点专家(O‘Dwyer博士)。AS 提出，这个项目有能力解释干扰RB-Cyclin D1的手段 改变改变人类疾病的疾病进展和治疗反应，并 戏剧性地改变了PCA管理。

项目成果

Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer.

• DOI: 10.1158/0008-5472.can-21-1159
• 发表时间: 2022-01-15
• 期刊: Cancer research
• 影响因子: 11.2