Targeting the ARF/CtBP Axis in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）是美国癌症死亡的第四大原因。胰腺癌的存活率异常低是由于这些肿瘤的侵袭性和转移性，以及它们对目前使用的化学和放射疗法的抗性。INK 4A/ARF基因座在80-95%的散发性PDAC中失活。40%的INK 4A/ARF失活病例中发生同步p53突变，表明这些肿瘤抑制因子在胰腺癌抑制中可能具有非重叠功能。越来越多的证据表明，ARF肿瘤抑制因子，激活p53在致癌应激反应，也具有p53的非依赖性功能，相关的抑制侵袭和转移。ARF抑制肺癌和结肠癌细胞系的侵袭和迁移，ARF无效肿瘤在小鼠肝细胞癌模型中表现出更强的侵袭性。ARF的这些p53非依赖性活性可以部分地通过其结合和拮抗辅阻遏物C-末端结合蛋白（CtBP）并通过去阻遏PTEN表达下调磷脂酰肌醇-3（PI 3）-激酶途径的能力来解释。因此，了解ARF/CtBP复合物的生物学功能及其对胰腺肿瘤进展和转移的潜在贡献可能会提供关键的见解，从而可能导致新的治疗方法。在这个建议中，我们将系统地分析ARF和CtBP的分子作用，具体到PI 3-激酶途径和胰腺癌的体外调节和小鼠转基因PDAC模型。CtBP的小分子抑制剂将在鼠PDAC模型中进行测试，这可能导致开发一类新的胰腺癌靶向治疗剂。这种治疗方法也可能在许多其他人类癌症中具有很大的实用性，其中CtBP由于ARF失活而失调。 公共卫生相关性：胰腺癌是人类最致命的癌症之一，通常会失去一种称为ARF的关键肿瘤抑制蛋白的功能。由于ARF的缺乏，一种称为C-末端结合蛋白（CtBP）的癌症促进蛋白被激活，导致癌细胞迁移更快，更具侵袭性，并且在恶劣环境中或暴露于癌症治疗时更容易存活。一种名为MTOB的药物可以阻断CtBP的作用，并可以在培养皿中杀死癌细胞，将在患胰腺癌的小鼠中测试其效果，作为未来在患有这种致命癌症的患者中测试这种药物或相关药物的前奏。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. The unusually low survival rate of pancreatic cancer is due to the aggressively invasive and metastatic nature of these tumors, and their resistance to currently used chemical and radiotherapies. The INK4A/ARF locus is inactivated in 80-95% of sporadic PDAC. Synchronous p53 mutations occur in 40% of cases with INK4A/ARF inactivation, suggesting that these tumor suppressors may have non-overlapping functions in pancreatic cancer suppression. Mounting evidence suggests that the ARF tumor suppressor, which activates p53 in response to oncogenic stress, also possesses p53-independent functions relevant to the suppression of invasion and metastasis. ARF inhibits invasion and migration in lung and colon cancer cell lines, and ARF-null tumors exhibit increased aggressiveness in a mouse model of hepatocellular carcinoma. These p53-independent activities of ARF can be explained, in part, by its ability to bind and antagonize the corepressor C-terminal Binding Protein (CtBP) and downregulate the phosphatidylinositol-3 (PI3)-kinase pathway via derepression of PTEN expression. Therefore, understanding the biologic function of ARF/CtBP complexes and their potential contribution to pancreatic tumor progression and metastasis may provide critical insights that could lead to novel therapeutics. In this proposal, we will systematically analyze the molecular actions of ARF and CtBP specific to regulation of the PI3-kinase pathway and pancreatic oncogenesis in vitro and in a murine transgenic PDAC model. A small molecule inhibitor of CtBP will be tested in the murine PDAC model that may lead to the development of a new class of targeted therapeutics in pancreatic cancer. Such therapeutics might also be of great utility in the many other human cancers where CtBP is deregulated due to ARF inactivation. PUBLIC HEALTH RELEVANCE: Pancreatic cancers, which are among the deadliest of human cancers, often lose the function of a key tumor suppressor protein called ARF. As a result of ARF's absence, a cancer promoting protein termed C-terminal Binding Protein (CtBP) is activated, causing cancer cells to migrate more rapidly, become more invasive, and survive more easily in hostile environments or when exposed to cancer therapeutics. A drug called MTOB that blocks the action of CtBP and can immobilize and kill cancer cells in a culture dish will be tested for its effect in mice that develop pancreatic cancer, as a prelude to future testing of this or related drugs in patients afflicted with this deadly form of cancer.