Genetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate Cancer

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• 批准号: 9000138
• 负责人: Daniel Edward Frigo
• 金额: $ 34.98万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-27 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000138
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Advanced Malignant Neoplasm; Androgen Receptor; Androgens; Animal Model; Benign; Biological Markers; Ca(2+)-Calmodulin Dependent Protein Kinase; CaM kinase I activator; Calcium/calmodulin-dependent protein kinase; Cancer Cell Growth; Cancer Etiology; Castration; Cell Culture Techniques; Cell model; Cessation of life; Clinical; Data; Development; Diagnosis; Disease; Disease Progression; Disease Resistance; Dissection; Drug Targeting; Enzymes; Exhibits; Fatty Acids; Fatty acid glycerol esters; Foundations; Genetic; Glucose; Goals; Growth; Health; In Vitro; Knowledge; Laboratories; Lead; LoxP-flanked allele; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolism; Modeling; Molecular Profiling; Mus; Outcome; Patients; Phosphotransferases; Pre-Clinical Model; Process; Prostate Cancer therapy; Protein Kinase; Publishing; Receptor Signaling; Recurrent disease; Regulation; Research; Resistance; Resolution; Risk; Role; Sampling; Second Primary Neoplasms; Signal Pathway; Signal Transduction; Source; Staging; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor-Derived; Validation; Work; Xenograft procedure; base; cancer initiation; castration resistant prostate cancer; cell motility; cohort; curative treatments; deprivation; drug discovery; fatty acid metabolism; genetic analysis; in vivo; in vivo Model; innovation; meetings; men; metabolic profile; metabolome; metabolomics; migration; mouse model; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prostate cancer cell; prostate cancer model; receptor; small molecule; subcutaneous; sugar; targeted treatment; therapeutic target; trait; tumor; tumor metabolism; tumor progression

DESCRIPTION (provided by applicant): While it is known that aberrant androgen receptor (AR) signaling is important for the development of prostate cancer, it has also become evident that AR signaling remains active and necessary in the deadly advanced stages of the disease. Despite the known importance of AR signaling in prostate cancer, the processes downstream of the receptor that drive disease progression remain poorly understood. This knowledge gap has precluded the development of novel therapies, particularly for the advanced stages of the disease for which there is currently no cure. Thus, the long-term goal is to develop new therapeutic approaches for the treatment of prostate cancer. Previous work from several independent laboratories has suggested AR signaling promotes prostate cancer growth, migration, invasion and altered metabolism in part through a Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKβAMP-activated protein kinase (AMPK) signaling pathway. The primary goal of this proposal is to use a combination of in vitro and in vivo models to define the specific role(s) of AR-mediated CaMKKβ signaling in prostate cancer and test whether it represents a viable drug target in preclinical genetic animal models. The central hypothesis is that the CaMKKβ axis promotes both glucose and fatty acid pathological metabolism and therefore represents a novel target for advanced prostate cancer therapy. This hypothesis is based on the preliminary and published data generated from the applicant's laboratory and is strongly supported by studies from other groups. The hypothesis will be tested with the following two specific aims: Aim 1: Determine the role of ARmediated CaMKKβ-AMPK signaling in prostate cancer cellular metabolism. Aim 2: Genetic dissection of the pathogenic role of CaMKKβ using preclinical mouse models of prostate cancer. Under the first aim, isolated cellular models of prostate cancer will be used to define the specific roles of CaMKKβ, AMPK and candidate downstream signaling targets in pathological metabolism using metabolic flux analysis and comprehensive metabolomic profiling techniques. In the second aim, a combination of genetic mouse models will be used to delineate the role of CaMKKβ in various stages of cancer progression. Further, tumors derived from these studies will be subjected to the metabolomic profiling described in the previous aim. The research is innovative because it tests the novel paradigm that AR signaling promotes prostate cancer progression through the promiscuous metabolism of both sugars and fats. Further, it tests this paradigm using mass spectroscopic techniques that, due to their enhanced resolution, will yield a comprehensive examination of the tumor metabolome. These studies are significant because they will conclusively determine whether CaMKKβ signaling is a viable therapeutic target in vivo and also identify potential metabolic biomarkers of its activity. Ultimately, it is anticipated that the completion of the proposed studis will set the foundation needed for subsequent drug discovery efforts.

描述（由申请人提供）：虽然已知异常的雄激素受体（AR）信号传导对于前列腺癌的发展很重要，但也明显的是，AR信号传导在该疾病的致命晚期阶段仍然活跃且必要。 AR信号传导在前列腺癌中的已知重要性，以及驱动疾病进展的受体下游过程仍然知之甚少，这种知识差距阻碍了新疗法的开发，特别是对于目前无法治愈的疾病的晚期阶段。 .因此，长期目标是开发治疗前列腺癌的新方法，多个独立实验室之前的工作表明，AR 信号传导在一定程度上通过以下方式促进前列腺癌的生长、迁移、侵袭和代谢。 Ca2+/钙调蛋白依赖性蛋白激酶β（CaMKKβAMP激活蛋白激酶（AMPK）信号通路）。该提案的主要目标是使用体外和体内模型的组合来定义AR介导的特定作用前列腺癌中的 CaMKKβ 信号传导，并测试它是否代表临床前遗传动物模型中可行的药物靶标。中心假设是 CaMKKβ 轴促进葡萄糖和脂肪酸病理代谢，因此代表了先进的新靶标。该假设基于申请人实验室生成的初步和已发表的数据，并得到其他小组研究的大力支持。该假设将通过以下两个具体目标进行测试： 目标 1：确定 AR 介导的 CaMKKβ 的作用。 -AMPK 信号在前列腺癌细胞代谢中的作用。 目标 2：使用前列腺癌临床前小鼠模型对 CaMKKβ 的致病作用进行基因剖析。的角色 使用代谢流分析和综合代谢组学分析技术研究病理代谢中的 CaMKKβ、AMPK 和候选下游信号传导靶标。在第二个目标中，将结合遗传小鼠模型来描述 CaMKKβ 在癌症进展的各个阶段中的作用。来自这些研究的肿瘤将接受先前目标中描述的代谢组学分析，该研究具有创新性，因为它测试了 AR 信号通过糖和蛋白质的混杂代谢促进前列腺癌进展的新范例。此外，它使用质谱技术测试了这一范例，由于其分辨率提高，将对肿瘤代谢组进行全面检查，这些研究意义重大，因为它们将最终确定 CaMKKβ 信号传导是否是体内可行的治疗靶点。最终，预计拟议研究的完成将为后续药物发现工作奠定基础。