A novel determinant of prostate cancer growth

前列腺癌生长的新决定因素

基本信息

批准号：
10589834
负责人：
Hannelore Heemers
金额：
$ 31.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589834
关键词：
Adult Affect American Behavior Benign Biological Assay Biology Bypass Cause of Death Cell Count Cell Cycle Cell Cycle Progression Cell Line Cell Proliferation Cell division Cells Cellular Morphology Cellular biology Cessation of life Clinical Coupled Development Disease Disease Progression Epithelial Cells Epithelium Event Foundations Gene Expression Genetic Goals Growth Human In Vitro Inhibition of Cell Proliferation Knowledge Laboratories Ligation Malignant Neoplasms Malignant neoplasm of prostate Mammals Mass Spectrum Analysis Mediating Metastatic Prostate Cancer Mission Mitotic Modality Molecular Molecular Biology Oncogenic Outcome Patients Phenotype Phosphorylation Phosphotransferases Proliferating Prostate Prostate Cancer therapy Protein Kinase Protein Kinase Interaction Protein-Serine-Threonine Kinases Public Health Research Resistance Role Serine Signal Transduction Testing Therapeutic Therapeutic Intervention Tissues Tumor Volume United States National Institutes of Health Work Xenograft Model Xenograft procedure advanced prostate cancer cancer therapy cell dedifferentiation cell growth citron rho-interacting kinase defined contribution improved in vivo inhibitor innovation insight kinase inhibitor loss of function men mortality mutational status new therapeutic target novel overexpression pharmacologic pluripotency prevent prostate cancer cell prostate cancer cell line prostate cancer progression protein expression standard of care stem cells targeted treatment therapeutic target therapy resistant tumorigenic

项目摘要

Project Summary/Abstract Prostate cancer (CaP) will cause the deaths of more than 33,000 American men in 2020 because systemic treatments for metastatic CaP fail. Actionable targets for novel treatments that work via entirely different mechanisms, bypass resistance to current therapies, and control biology that drives CaP progression are needed urgently to improve patient survival. The long-term goal is to target the mechanism(s) that control CaP cell proliferation and CaP growth for therapeutic intervention. Our objective here is to derive the insights needed to determine the feasibility and applicability of inhibiting the action of the mitotic kinase citron kinase (CIT) as novel CaP treatment. We hypothesize that the mechanism(s) by which CIT, and its kinase activity, control CaP cell proliferation can be exploited as alternative CaP treatment to overcome acquired resistance to conventional CaP therapies. This hypothesis is formulated based on preliminary work produced in our laboratory, which identified CIT and its kinase activity as a novel critical determinant of CaP growth. The rationale is that this work may lay the foundation of a much-needed novel CaP therapeutic that targets specifically CaP growth during disease progression. We will test this hypothesis by pursuing 3 Specific Aims: 1) to define the mechanism(s) that control CIT protein expression, 2) to determine the manner in which CIT conveys aggressive CaP behavior, and 3) to determine the therapeutic potential of targeting CIT during CaP progression. Aim 1 will use molecular biology and cell biology approaches to delineate the molecular mechanism by which the novel E2F2-Skp2 signaling axis induces CIT protein levels, and specifically the role of Skp2-mediated degradation of p27 herein. In Aim 2, we will define the manner in which CIT conveys aggressive CaP behavior by isolating the CIT protein interactome and CIT kinase substrates that mediate CaP cell proliferation. Integrated kinase substrate assays and proximity ligation assays coupled with mass spectrometry will be performed. Aim 3 will define the therapeutic potential of genetic or pharmacological CIT inhibition on the growth of CaP cell line xenografts, PDXs and fresh patient tissue explants before and after ADT, and compare its efficacy to that achieved by the standard of care. The proposed research is innovative because it focuses on an entirely different approach to CaP treatment: targeting the action of a novel regulator of CaP growth to inhibit progression of advanced CaP and to bypass CaP treatment resistance. This contribution is significant because it is the first step in a continuum of research that is expected to lead to the development of novel treatment modalities that target specifically the molecular mechanisms that control lethal CaP progression. With respect to expected outcomes, the proposed studies will delineate how CIT controls CaP cell proliferation and establish its value as much-needed therapeutic target during CaP progression. These results will have a significant positive impact because they will fundamentally advance knowledge of the mechanisms that control CaP growth, in general, and provide CIT as an entirely new and functionally distinct target for much-needed novel Cap treatments, specifically.

项目摘要/摘要前列腺癌（CAP）将在2020年导致33,000多名美国男性死亡，因为转移帽的治疗失败。可行的目标，用于完全不同的新型治疗方法需要机理，绕过对当前疗法的抵抗力以及控制限制进展的生物学紧急改善患者的生存。长期目标是针对控制盖电池的机制治疗干预措施的增殖和CAP生长。我们的目标是获得所需的见解确定抑制有丝分裂激酶Citron激酶（CIT）作用的可行性和适用性帽处理。我们假设CIT及其激酶活性的机制，控制盖细胞可以利用增殖作为替代帽处理，以克服对常规帽的获得的抵抗力疗法。该假设是根据我们实验室中生产的初步工作提出的，该工作确定 CIT及其激酶活性是CAP生长的新型关键决定因素。理由是这项工作可能是急需的新型帽治疗的基础进展。我们将通过追求3个具体目标来检验这一假设：1）定义控制机制 CIT蛋白表达，2）确定CIT传达攻击性帽行为的方式，以及3）确定靶向CIT在帽进展过程中的治疗潜力。 AIM 1将使用分子生物学细胞生物学方法是描述新型E2F2-SKP2信号轴的分子机制诱导CIT蛋白水平，特别是SKP2介导的p27降解的作用。在AIM 2中，我们将通过隔离CIT蛋白相互作用组来定义CIT传达攻击性帽行为的方式和CIT激酶底物介导盖细胞增殖。集成激酶底物测定和接近性连接测定将与质谱进行结合。 AIM 3将定义遗传或药理CIT抑制对盖细胞系异种移植物，PDX和新鲜患者组织的生长的抑制 ADT之前和之后的外植体，并将其功效与护理标准实现的功效进行比较。提议研究之所以创新，是因为它专注于完全不同的限额处理方法：针对新型帽生长调节剂的作用，以抑制晚期CAP的进展和绕过帽帽处理反抗。这项贡献是重要的，因为它是一项连续研究的第一步导致发展新型治疗方式的发展，这些方法专门针对分子机制控制致命的帽进展。关于预期的结果，拟议的研究将描述如何 CIT控制帽细胞增殖并建立其在CAP期间急需的治疗靶标的值进展。这些结果将产生重大的积极影响，因为它们将从根本上进步了解控制上限增长的机制，并提供CIT作为全新的机制特别是急需的新型帽处理的功能截然不同的目标。