Role of Transcriptional Corepressor CtBP1 in Prostate Cancer Progression

描述(申请人提供)：前列腺癌是美国最常见的癌症，也是男性癌症死亡的第二大原因。这种疾病的分子病因差异很大，目前的治疗方法对晚期转移性疾病的失败率很高。更好地了解调节前列腺癌进展的潜在分子事件将显著提高我们更准确地诊断、分类和治疗前列腺癌患者的能力。通过检查与正常细胞相比，癌细胞中调控失调的分子通路，我们可以确定驱动癌症进展的特定遗传损伤。然后，这些遗传损伤可以成为适当治疗的目标，要么是现有的化合物，要么是新药的开发。我们的初步工作发现，转录辅阻遏子CtBP1在侵袭性前列腺癌中过表达，数据表明CtBP1是前列腺癌细胞生存所必需的。CtBP1在癌细胞中的缺失在体外抑制细胞的增殖和侵袭，在体内也抑制肿瘤的转移。这些观察表明，前列腺癌细胞可能严重依赖CtBP1生存。这项研究的基本假设是，CtBP1可能是诊断时侵袭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是癌症治疗的有效靶点，现有的或新的化合物抑制CtBP1的活性可能被用于有效治疗前列腺癌患者的亚群。本研究的具体目的是：1.研究CtBP1在前列腺癌中的表达和定位。CtBP1的表达将在一大批前列腺癌中进行评估，以测试CtBP1表达作为诊断和预后标记物的实用性。目的2.探讨CtBP1在侵袭性前列腺癌中的作用。这一目标将提供对CtBP1在前列腺癌进展中的作用的洞察。此外，这一目标将为靶向CtBP1进行治疗干预提供可能的途径。目的3.确定和鉴定CtBP1在前列腺癌进展中起作用的结合伙伴和靶点。这里的一个次要目标将集中在鉴定可能对CtBP1活性至关重要的CtBP1结合蛋白，并鉴定靶向CtBP1进入胞浆的细胞蛋白。此外，我们将评估由CtBP1调控的基因，然后进行生物学验证，重点是与治疗相关的靶点。总之，这项建议将研究CtBP1的表达和细胞定位，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，我们还将探讨其在前列腺癌诊断和预后方面的临床潜力，我们预计发现CtBP1‘S在前列腺癌中的作用将有助于发现和/或开发潜在的治疗抑制物。

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.