Phosphatidylinositol 3-kinase and prevention of pancreatic cancer

描述（由申请人提供）：胰腺导管腺癌（PDA）是一种致命的人类癌症，总体5年生存率低于5%。迫切需要对这种疾病采取更好的预防和治疗战略。与大多数其他实体恶性肿瘤不同，PDA在遗传上具有惊人的同质性。绝大多数（>90%）的人类PDA含有独特的遗传特征：它们具有Kras原癌基因的激活突变。Kras激活在这种恶性肿瘤的发展中的关键作用得到了研究的支持，这些研究表明，在胰腺细胞中表达激活的Kras突变体的小鼠会发展出胰腺癌患者中常见的全谱癌前和恶性肿瘤。这一建议解决了一个重要的研究问题，具有很高的翻译价值：下调磷脂酰肌醇3-激酶（PI 3 K）p1101阻止或阻断致癌Kras诱导的胰腺癌的发展？目的1使用分子和细胞研究来深入了解PI 3 K p1101如何调节和受Kras调节。这些实验的结果将增加我们关于如何治疗所有Kras诱发的癌症的知识。目的2在Kras和p53突变诱导的PDA小鼠模型中使用PI 3 K p1101的基因消融来测试p110 a是否是胰腺癌的可行治疗靶点。目的3：用药理学方法研究化学抑制PI 3 K是否是预防Kras诱导肿瘤中PDA发展的安全方法。这项研究的结果对现有PI 3 K抑制剂的测试和该类新型化合物的开发具有明显的临床意义。我们的动物研究的成功完成将导致研究天然和合成的PI 3 K抑制剂作为人类胰腺癌的化学预防干预。公共卫生相关性：胰腺导管腺癌是一种致命的人类癌症，总体5年生存率低于5%。这种疾病每年导致约33，000名美国人死亡，使其成为癌症死亡的第四大原因，迫切需要更好的预防和治疗策略。该项目旨在了解磷脂酰肌醇3-激酶（PI 3 K）生化途径在介导胰腺肿瘤形成中的重要性。我们的研究的成功完成将导致PI 3 K抑制剂作为人类胰腺癌预防干预措施的研究。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is a deadly human cancer with a overall 5-year survival rate of less than 5%. Better preventive and treatment strategies are desperately needed for this disease. Unlike most other solid malignancies, PDA is surprisingly homogeneous genetically. The great majority (>90%) of human PDA contain a unique genetic signature: they have activating mutations of the Kras proto-oncogene. The critical role of Kras activation in the development of this malignancy is supported by studies showing that mice expressing an activated Kras mutant in pancreatic cells develop the full spectrum of premalignant and malignant tumors commonly found in pancreatic cancer patients. This proposal addresses an important research question with high translational value: does downregulation of phosphatidylinositol 3-kinase (PI3K) p1101 prevent the development or block the progression of pancreatic cancer induced by oncogenic Kras? Aim 1 uses molecular and cellular studies to gain mechanistic insight into how PI3K p1101 regulates and is regulated by Kras. Results from these experiments will increase our knowledge regarding how to treat all Kras-induced cancers. Aim 2 uses genetic ablation of PI3K p1101 in a mouse model of PDA induced by Kras and p53 mutations to test if p110a is a viable therapeutic target in pancreatic cancer. Aim 3 uses a pharmacological approach to investigate if chemical inhibition of PI3K prevents is a safe approach to prevent the development of PDA in the Kras induced tumors. Results from this study have obvious clinical implications for the testing of existing PI3K inhibitors and for the development of novel compounds in this class. Successful completion of our animal studies should lead to investigation of natural and synthetic PI3K inhibitors as a chemopreventive intervention for pancreatic cancer in humans. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma is a deadly human cancer with an overall 5-year survival rate of less than 5%. Better preventive and treatment strategies are desperately needed for this disease that kills ~33,000 Americans a year, making it the fourth leading cause of cancer death. This project is directed at understanding the importance of the phosphatidylinositol 3-kinase (PI3K) biochemical pathway in mediating pancreatic tumor formation. Successful completion of our studies should lead to investigation of PI3K inhibitors as preventive interventions for pancreatic cancer in humans.