Targeting the ARF/CtBP Axis in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）是美国第四大癌症死亡原因。胰腺癌异常低的生存率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治疗的耐药性。INK4A/ARF基因座在80-95%的散发性PDAC中失活。40%的INK4A/ARF失活病例发生同步p53突变，提示这些肿瘤抑制因子在胰腺癌抑制中可能具有不重叠的功能。越来越多的证据表明，ARF肿瘤抑制因子，激活p53以响应致癌应激，也具有与p53无关的功能，与抑制侵袭和转移有关。ARF抑制肺癌和结肠癌细胞系的侵袭和迁移，在小鼠肝细胞癌模型中，ARF缺失的肿瘤表现出更高的侵袭性。ARF的这些不依赖p53的活性可以部分解释为其结合和拮抗协同抑制因子c -末端结合蛋白（CtBP）的能力，并通过降低PTEN表达下调磷脂酰肌醇-3 （PI3）激酶途径。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为开发新的治疗方法提供重要见解。在本文中，我们将在体外和小鼠转基因PDAC模型中系统地分析ARF和CtBP特异性调节pi3激酶途径和胰腺肿瘤发生的分子作用。一种CtBP的小分子抑制剂将在小鼠PDAC模型中进行测试，这可能会导致胰腺癌靶向治疗的新类别的发展。这种治疗方法也可能在许多其他人类癌症中有很大的效用，其中由于ARF失活而导致CtBP失控。

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.