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

遗传

• 批准号: 9207070
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207070
• 关键词: 5' -AMP-activated protein kinase; Advanced Malignant Neoplasm; Androgen Receptor; Androgens; Animal Genetics; 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; In Vitro; Knowledge; Laboratories; Lead; LoxP-flanked allele; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolism; Modeling; Molecular Profiling; Mus; Outcome; Pathogenicity; Pathologic; Patients; Pharmacology; Phosphotransferases; Pre-Clinical Model; Process; Prostate Cancer therapy; Protein Kinase; Publishing; Receptor Signaling; Recurrent disease; Regulation; Research; Resistance; Resolution; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Source; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor-Derived; Validation; Work; Xenograft procedure; base; cancer initiation; castration resistant prostate cancer; cell growth; cell motility; cohort; curative treatments; deprivation; drug discovery; fatty acid metabolism; in vivo; in vivo Model; innovation; men; metabolic profile; metabolome; metabolomics; migration; mouse model; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prostate cancer cell; prostate cancer model; public health relevance; 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（由适用提供）：虽然众所周知，异常的雄激素受体（AR）信号对于前列腺癌的发展很重要，但它也已成为证据，表明AR信号在该疾病的致命晚期阶段保持活跃和必要。尽管AR信号在前列腺癌中的重要性已知，但驱动疾病进展的受体下游的过程仍然知之甚少。这种知识差距排除了新疗法的发展，特别是对于目前尚无治愈的疾病的晚期阶段。这是长期目标是开发用于治疗前列腺癌的新治疗方法。几个独立实验室的先前工作表明，AR信号促进了前列腺癌的生长，迁移，侵袭和代谢改变，部分通过 Ca2+/钙调蛋白依赖性蛋白激酶激酶β（CAMKKβAMP激活蛋白激酶（AMPK）信号传导途径。该建议的主要目标是使用体外和体内模型组合来定义AR-MIDIEDCAMKKβ信号在前列腺癌中的特定作用，以确定前列性的动物癌症，是否代表性地构成了预先构成的良好的药物。假设CAMKKβ轴促进了葡萄糖和脂肪酸病理代谢，因此代表了先进的前列腺癌治疗的新目标。前列腺癌细胞代谢。在第一个目标下，将使用孤立的前列腺癌细胞模型来定义 CAMKKβ，AMPK和候选候选信号传导靶标在病理代谢中使用代谢通量分析和全面的代谢分析技术。在第二个目标中，将使用遗传小鼠模型的组合来描述CAMKKβ在癌症进展的各个阶段的作用。此外，从这些研究中得出的肿瘤将受到先前目的中描述的代谢组分析。这项研究具有创新性，因为它测试了新的范式，即AR信号传导通过糖和脂肪的混杂代谢促进前列腺癌的进展。此外，它使用质谱技术测试了这种范式，由于分辨率增强，它将对肿瘤代谢组进行全面检查。这些研究之所以重要，是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标，并且还确定其活性的潜在代谢生物标志物。归根结底，预计拟议的研究员的完成将为随后的药物发现工作奠定基础。