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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在了解去势抵抗性前列腺癌 (CRPC) 进展方面的最新进展导致开发可略微提高总体生存率的治疗方法；然而，大多数患者 CRPC 在 2-3 年内死于疾病，表明需要精准医疗的衡量标准，并且在这里，我们提出了一种雄心勃勃的分层和增强方法。根据我们研究的细胞周期改变，治疗转移性 CRPC 以改善治疗结果最近发现的研究将探索针对 PCa 的未触及领域。基于治疗的管理，并将在此提供基于亚型的首次治疗评估此外，所描述的研究可以提供第一个用于分层的生物标志物。前列腺癌治疗，并改善晚期疾病患者的治疗。研究结果强烈表明 RB-cyclin D1/CDK4 轴的改变在疾病中发挥着重要作用对这些改变进展的分子研究为疾病提供了合理的基础晚期前列腺癌的分层和改进管理这一假设将受到挑战。首先，在两项资助的临床试验的基础上，我们将使用新颖的活检材料。疾病模型和联合临床试验挑战 RB-细胞周期蛋白 D1/CDK4 轴可以被开发作为反应的生物标志物和治疗分层的指标（目标 1）。有可能为近期患者带来好处，并且可以确定第一个用于个性化治疗的生物标志物其次，将使用稳健的模型来探究晚期 PCa 的分子基础。对针对 RB 和/或细胞周期蛋白 D1 状态改变的治疗的反应（目标 2）。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最后，针对 Rb-cyclin D1/CDK4 轴迫使肿瘤依赖。 G2/M 细胞周期蛋白依赖性激酶上的细胞 - 因此制定了利用该细胞周期的计划依赖性，目标是发现新的方法，以最大限度地提高细胞治疗效果 RB-cyclin D1/CDK4 改变（目标 3）晚期 PCa 临床管理的领导者和新型临床试验的先驱（Kelly 博士），以及领先的 AR 生物学家，在研究细胞周期调控和 PCa 相关细胞周期方面拥有丰富的专业知识改变（Knudsen 博士），以及细胞周期改变临床靶向专家（O’Dwyer 博士）。提议，该项目有能力阐明扰动 Rb-cyclin D1 的方式改变会改变人类疾病的疾病进展和治疗反应，并显着改变 PCa 管理。