Role of Transcriptional Corepressor CtBP1 in Prostate Cancer Progression

描述（由申请人提供）：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有显著的失败率。更好地了解调控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。通过检查癌细胞中与正常细胞相比失调的分子途径，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治疗的目标，要么使用现有的化合物，要么为开发新药提供信息。我们的初步工作发现，转录共抑制因子CtBP1在侵袭性前列腺癌中过表达，数据表明CtBP1是前列腺癌细胞存活所必需的。癌细胞中CtBP1的缺失抑制了细胞的增殖和体外侵袭以及体内转移。这些观察结果表明，前列腺癌细胞可能严重依赖CtBP1存活。本研究的基本假设是CtBP1可能是侵袭性前列腺癌诊断时的重要生物标志物，可能影响患者的临床管理。作为一种功能性脱氢酶，CtBP1是一种可行的癌症治疗靶点，现有或新化合物抑制CtBP1活性可能用于有效治疗前列腺癌患者亚群。本建议的具体目标是：目标1。CtBP1在前列腺癌中的表达和定位CtBP1的表达将在一个大型前列腺癌队列中进行评估，以测试CtBP1表达作为诊断和预后标志物的效用。目标2。评估CtBP1在侵袭性前列腺癌中的功能作用。这一目标将有助于深入了解CtBP1在前列腺癌进展中的作用。此外，这一目标将为靶向CtBP1进行治疗干预提供可能的途径。目标3。鉴定和表征CtBP1在前列腺癌进展中发挥作用的结合伙伴和靶标。这里的一个次要目标将集中在鉴定CtBP1结合蛋白，这可能是CtBP1活性所必需的，并鉴定靶向CtBP1到细胞质的细胞蛋白。此外，我们将评估CtBP1调控的基因，然后进行生物学验证，重点关注治疗相关靶点。综上所述，本课题将研究CtBP1的表达和细胞定位，确定其在肿瘤侵袭转移中的功能作用。提案还确定了CtBP1的结合伙伴和下游靶点。此外，我们将研究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在前列腺癌中的作用将有助于识别和/或开发潜在的治疗抑制剂。

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.