Role of Transcriptional Corepressor CtBP1 in Prostate Cancer Progression

转录辅阻遏物 CtBP1 在前列腺癌进展中的作用

• 批准号: 8458062
• 负责人: Sooryanarayana Varambally
• 金额: $ 30.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458062
• 关键词: Binding; Binding Proteins; Biological; Biological Markers; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cell Proliferation; Cell Survival; Cell physiology; Cessation of life; Clinical; Clinical Management; Cytoplasm; Cytosol; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disseminated Malignant Neoplasm; EZH2 gene; Early Diagnosis; Enzymes; Etiology; Event; Failure; Gene Expression Profiling; Genes; Genetic; Histones; Hormonal; In Vitro; Lesion; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Neoplasm Metastasis; Normal Cell; Oncogenic; Operative Surgical Procedures; Outcome; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prognostic Marker; Proteins; Role; Second Primary Cancers; Sum; Testing; Therapeutic Intervention; Time; Transcription Repressor/Corepressor; Tumor Cell Invasion; United States; Validation; Work; advanced disease; aggressive therapy; cancer cell; cohort; gene repression; hormone refractory prostate cancer; in vivo; inhibitor/antagonist; insight; men; novel; outcome forecast; overexpression; prostate cancer cell; stem; success; therapeutic target; transcription factor; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer and the second leading cause of cancer death for men in the United States. The molecular etiology of this disease varies widely and current therapies have a significant failure rate for advanced metastatic disease. A better understanding of the underlying molecular events that regulate prostate cancer progression will significantly enhance our ability to more accurately diagnose, classify and treat prostate cancer patients. By examining the molecular pathways that are dysregulated in cancer cells compared to normal cells, we can identify the specific genetic lesions that drive cancer progression. These genetic lesions can then be targets for appropriate therapies, either with existing compounds or inform the development of novel drugs. Our initial work found that the transcriptional corepressor CtBP1 is overexpressed in aggressive prostate cancer and data suggest that CtBP1 is required for prostate cancer cell survival. Loss of CtBP1 in cancer cells inhibits cell proliferation and invasion in vitro as well as metastasis in vivo. These observations indicate that prostate cancer cells may be critically dependent on CtBP1 for survival. The underlying hypothesis of this study is that CtBP1 may be an important biomarker for aggressive prostate cancer at the time of diagnosis that could impact the clinical management of patients. Being a functional dehydrogenase enzyme, CtBP1 serves as a viable therapeutic target in cancer and inhibition of CtBP1 activity by existing or novel compounds can potentially be used to effectively treat sub-sets of prostate cancer patients. The specific aims of this proposal are: Aim 1. Characterize CtBP1 expression and localization in prostate cancer. The expression of CtBP1 will be evaluated in a large cohort of prostate cancers to test the utility of CtBP1 expression as a diagnostic and prognostic marker. Aim 2. Evaluate the functional role of CtBP1 in aggressive prostate cancer. This aim will provide insight into the role of CtBP1 in prostate cancer progression. In addition, this aim will provide possible avenue to target CtBP1 for therapeutic interventions. Aim 3. Identify and characterize binding partners and targets of CtBP1 that play a role in prostate cancer progression. A sub aim here will focus on identification CtBP1 binding proteins that may be essential for CtBP1 activity and identify cellular proteins that target CtBP1 to the cytosol. Additionally, we will evaluate the genes regulated by CtBP1 followed by biological validation with an emphasis on therapeutically relevant targets. In sum, this proposal will investigate CtBP1 expression and cellular localization as well as determine its functional role in tumor invasion and metastasis. Proposal also identifies the binding partners and downstream targets of CtBP1. Additionally, we will investigate its clinical potential in the diagnosis and prognosis of prostate cancer, and we anticipate that uncovering CtBP1's role in prostate cancer will aid in the identification and/or development of potential inhibitor for treatment.

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症，也是癌症死亡的第二大原因。该疾病的分子病因差异很大，当前疗法对于晚期转移性疾病具有显着的衰竭率。对调节前列腺癌进展的基本分子事件的更好理解将显着增强我们更准确地诊断，分类和治疗前列腺癌患者的能力。通过检查癌细胞与正常细胞相比在癌细胞中失调的分子途径，我们可以确定驱动癌症进展的特定遗传病变。然后，这些遗传病变可以成为适当疗法的靶标，无论是现有化合物还是通知新药的发展。我们的最初工作发现，转录核心CTBP1在侵略性的前列腺癌中过表达，数据表明，前列腺癌细胞存活需要CTBP1。癌细胞中CTBP1的丧失抑制了体内的细胞增殖和体外侵袭和转移。这些观察结果表明，前列腺癌细胞可能主要取决于CTBP1的生存。这项研究的基本假设是，在诊断时，CTBP1可能是攻击性前列腺癌的重要生物标志物，可能会影响患者的临床治疗。作为一种功能性脱氢酶，CTBP1是癌症中可行的治疗靶标，并可能使用现有或新颖化合物抑制CTBP1活性，可用于有效治疗前列腺癌患者的子群。该提案的具体目的是：目标1。表征CTBP1表达和前列腺癌中的定位。 CTBP1的表达将在大量前列腺癌中进行评估，以测试CTBP1表达作为诊断和预后标记的效用。 AIM 2。评估CTBP1在攻击性前列腺癌中的功能作用。该目标将洞悉CTBP1在前列腺癌进展中的作用。此外，此目标将为您的治疗干预措施提供目标CTBP1的可能性。目标3。确定并表征CTBP1的结合伴侣和目标，这些伴侣在前列腺癌的进展中发挥作用。此处的一个目标将重点放在鉴定CTBP1结合蛋白上，这可能是CTBP1活性至关重要的，并鉴定靶向CTBP1至细胞质的细胞蛋白。此外，我们将评估由CTBP1调节的基因，然后进行生物学验证，重点是治疗相关靶标。总而言之，该建议将研究CTBP1表达和细胞定位，并确定其在肿瘤侵袭和转移中的功能作用。提案还确定了CTBP1的结合伙伴和下游目标。此外，我们将研究其在前列腺癌诊断和预后中的临床潜力，我们预计发现CTBP1在前列腺癌中的作用将有助于鉴定和/或开发潜在的抑制剂进行治疗。