Novel Molecular Therapies of Prostate Cancer

前列腺癌的新型分子疗法

基本信息

批准号：
9324925
负责人：
Dario C Altieri
金额：
$ 123.98万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-09 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324925
关键词：
ART protein Address Back Bioenergetics Biology Biometry Biostatistics Core Blocking Antibodies Budgets Cancer Patient Clinic Collaborations Competence Credentialing Data Data Analyses Diagnosis Disease Distant Enhancers Ensure Environment Evaluation Genetic Transcription Goals Grant Heart Homing Immune response Immunosuppression Immunosuppressive Agents Immunotherapy Integrin-mediated Cell Adhesion Pathway Integrins Investigational Drugs Knowledge Link Location Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Mass Spectrum Analysis Mechanics Mediator of activation protein Membrane Metastatic to Mitochondria Modeling Molecular Morbidity - disease rate Myelogenous Neoplasm Metastasis Organ Paper Pathway interactions Patients Peer Review Philadelphia Process Productivity Prostate Cancer therapy Proteome Proteomics Publications Publishing Recommendation Recording of previous events Research Research Infrastructure Research Personnel Review Literature Role Sampling Services Shapes Signal Transduction Site Stress Suppressor-Effector T-Lymphocytes Testing Time Tumor Biology Work advanced disease anticancer research bone cell motility clinical practice collaborative environment cost cost effective design exosome experience genetic regulatory protein geographically distant inhibitor/antagonist innovation intercellular communication metabolomics mitochondrial metabolism mortality neoplastic cell novel novel therapeutics oncology programs prostate cancer cell protein complex research clinical testing response spatiotemporal therapeutic candidate therapeutic target tumor metabolism tumor progression

项目摘要

OVERALL - PROJECT SUMMARY The present application is the continuation of CA140043 for a new grant cycle. Progress made during the past four years identified a new role of mitochondrial metabolism in tumor progression (Project 1), dissected the function of integrin-mediated cell adhesion in prostate cancer invasion (Project 2), and elucidated transcriptional circuitries of bone metastatic disease (Project 3). As a whole, the Program had a multiplier effect for prostate cancer research. The original specific aims were met, impactful collaborative publications appeared in the peer-reviewed literature, and a translational goal of merging mechanistic understanding of prostate cancer progression with credentialing new therapeutic candidates for metastatic disease was fulfilled. Building on these accomplishments, the present continuation application has been significantly restructured. Brought back to a single physical location in Philadelphia with a rich environment for prostate cancer research, the continuation of CA140043 stresses innovation and focuses on emerging new paradigms of prostate cancer progression. The overarching goal is to elucidate new mechanisms of metastatic competency in prostate cancer, and identify “actionable” therapeutic targets for late'stage disease. Project 1 (Project Leader, Dr. Altieri) will define a novel pathway of spatiotemporal mitochondrial bioenergetics, which fuels membrane dynamics of cell motility and prostate cancer invasion. Project 2 (Project Leader, Dr. Languino) will elucidate the role of prostate cancer-released exosomes as novel mediators of integrin-dependent tumor cell motility. Project 3 (Project Leader, Dr. Gabrilovich) is a new addition to the Program, and will characterize the role of mitochondrial reprogramming in the function and homing of Myeloid-Derived Suppressor Cells (MDSC) to primary and pre-metastatic tumor sites during prostate cancer progression. An Administration and Biostatistics core (Core A) will function as a research enhancer for the overall Program, ensuring scientific integration, input from advisory bodies, access to patient material, biostatistics support for the three Projects, and timely financial and administrative oversight. A unique Mass Spectrometry core (Core B) will support metabolomics profiling and quantitative proteomics of regulatory protein complexes, secretomes and proteomes in prostate cancer cells and MDSC. Overall, the Program builds on a decades-long history of collaboration among its experienced investigators, a cost-effective organizational infrastructure designed to maximize integration and reduce redundancies, and an intellectually-stimulating environment for collaborative prostate cancer research. This integrated discovery platform was enthusiastically received by the reviewers during the first evaluation of the application. Critical Program components (Cores, Integration) were found to have essentially no flaws, and recommendations with the experimental approaches of the three Projects have been addressed with inclusion of considerable new preliminary data, refocusing of experimental plans, and clarification of data analysis and interpretation. In line with the strong productivity of CA140043 during its first budget cycle, the investigators on this Program have continued to assiduously work together throughout the review process, publishing five additional collaborative papers, with five more collaborative manuscripts currently under review. Building on these accomplishments, and thank to the input of the reviewers, the amended application is now ideally poised to fulfill its specific aims, deliver on scientific innovation and transform our understanding of metastatic competency in prostate cancer. The results have the potential to revolutionize clinical practice in advanced disease, especially now that immunotherapy has emerged as a promising treatment in several malignancies, and targeting tumor metabolism has passed proof-of-concept and entered clinical testing.

总体 - 项目摘要本申请是新的赠款周期的CA140043的延续。在过去的四年中取得的进展确定了线粒体代谢在肿瘤进展中的新作用（项目1），解剖了整联蛋白介导的细胞粘附在前列腺癌入侵中的功能（项目2）和阐明的骨转移性疾病的转录回路（项目3）。总体而言，该计划对前列腺癌研究具有乘数效应。最初的具体目的是满足的，有影响力的合作出版物出现在经过同行评审的文献中，以及将机械理解与前列腺癌进展的机械理解与证书的转移性疾病的新治疗候选者的转化目标。在这些成就的基础上，当前的延续申请已得到了大量恢复。 CA140043的延续重新带回了费城的一个物理位置，并具有丰富的前列腺癌研究环境。总体目标是阐明前列腺癌中转移能力的新机制，并确定晚期疾病的“可行”治疗靶标。项目1（项目负责人，Altieri博士）将定义一种新型的空间暂时线粒体生物能学途径，该途径促进细胞运动和前列腺癌入侵的膜动力学。 Project 2（项目负责人，Leganino博士）将阐明前列腺癌释放的外泌体作为整合素依赖性肿瘤细胞运动的新型介体的作用。项目3（项目负责人Gabrilovich博士）是该程序的新补充，将表征线粒体重编程在髓样衍生的抑制细胞（MDSC）中对原发性和前分离肿瘤部位在前列腺癌进展过程中的作用和归位。管理和生物统计学核心（核心A）将充当整个计划的研究增强剂，确保科学整合，咨询机构的投入，访问患者材料，对这三个项目的生物统计学支持以及及时的财务和行政监督。独特的质谱核心（核心） b）将支持前列腺癌细胞和MDSC中调节蛋白复合物，秘密组和蛋白质组织的代谢组学分析和定量蛋白质组学。总体而言，该计划建立在其经验丰富的研究人员之间长达数十年的合作历史的基础上，这是一种具有成本效益的组织基础设施，旨在最大化整合和减少冗余，以及为协作前列腺癌研究的智能刺激环境。审稿人在对应用程序的第一次评估中热情地收到了这个集成的发现平台。发现关键的程序组件（核心，集成）基本没有缺陷，并且已经解决了三个项目的实验方法的建议，其中包括考虑新的初步数据，重新调整实验计划以及澄清数据分析和解释。与CA140043在其第一个预算周期中的强大生产率一致，该计划的调查人员在整个审核过程中继续协助合作，发表了另外五篇协作论文，目前正在审查五个协作手稿。在这些成就的基础上，并且感谢审稿人的投入，修订后的申请现在是理想的中毒，可以实现其特定目标，实现科学创新并改变我们对前列腺癌转移性能力的理解。该结果有可能彻底改变晚期疾病的临床实践，尤其是现在，免疫疗法已成为几种恶性肿瘤的证明治疗方法，而靶向肿瘤代谢已经通过了概念验证并进行了临床测试。