Phosphatidylinositol 3-kinase and prevention of pancreatic cancer

描述(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年生存率不到5%。对于这种疾病，迫切需要更好的预防和治疗策略。与大多数其他实体恶性肿瘤不同，PDA在基因上惊人地同质。绝大多数(&gt；90%)的人类PDA包含一个独特的遗传特征：他们具有Kras原癌基因的激活突变。研究表明，在胰腺癌患者中表达激活的Kras突变体的小鼠会发展出常见于胰腺癌患者的癌前和恶性肿瘤的全谱，这支持了Kras激活在这种恶性肿瘤的发展中的关键作用。这一建议解决了一个具有很高翻译价值的重要研究问题：磷脂酰肌醇3-激酶(PI3K)p1101的下调是预防还是阻止致癌Kras诱导的胰腺癌的发生？目的1利用分子和细胞研究来深入了解PI3K p1101是如何调控和被Kras调控的。这些实验的结果将增加我们关于如何治疗所有Kras诱导的癌症的知识。目的在Kras和P53基因突变诱导的小鼠PDA模型中，通过基因消融PI3K p1101来验证p110a是否是治疗胰腺癌的有效靶点。目的用药理学方法研究化学抑制PI3K是否是预防Kras诱导的肿瘤中PDA发生的安全方法。这项研究的结果对现有的PI3K抑制剂的测试和这类新化合物的开发具有明显的临床意义。成功完成我们的动物研究应该会导致研究天然和合成的PI3K抑制剂作为人类胰腺癌的化学预防干预措施。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年生存率不到5%。对于这种每年导致约3.3万美国人死亡的疾病，迫切需要更好的预防和治疗策略，使其成为癌症死亡的第四大原因。本项目旨在了解磷脂酰肌醇3-激酶(PI3K)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对PI3K抑制剂作为预防人类胰腺癌干预措施的研究。

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.