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5年生存率低于5%。迫切需要更好的预防和治疗战略来对付这种疾病。与大多数其他实体恶性肿瘤不同，PDA在基因上具有惊人的同质性。绝大多数（约90%）的人类PDA包含一个独特的遗传特征：它们具有Kras原癌基因的激活突变。研究表明，在胰腺细胞中表达激活的Kras突变体的小鼠发展为胰腺癌患者常见的全谱癌前和恶性肿瘤，支持了Kras激活在这种恶性肿瘤发展中的关键作用。该建议解决了一个具有高翻译价值的重要研究问题：下调磷脂酰肌醇3-激酶（PI3K） p1101是否可以预防或阻断由致癌Kras诱导的胰腺癌的发生或进展？Aim 1使用分子和细胞研究来获得PI3K p1101如何调节和受Kras调节的机制。这些实验的结果将增加我们对如何治疗所有kras诱导的癌症的认识。在Kras和p53突变诱导的PDA小鼠模型中，Aim 2通过基因消融PI3K p1101来检测p110a是否是胰腺癌的可行治疗靶点。Aim 3使用药理学方法来研究化学抑制PI3K阻止是否是一种安全的方法来阻止Kras诱导的肿瘤中PDA的发展。本研究结果对现有PI3K抑制剂的检测和该类新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对天然和合成PI3K抑制剂作为人类胰腺癌化学预防干预的研究。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%。我们迫切需要更好的预防和治疗策略，因为这种疾病每年导致约3.3万美国人死亡，使其成为癌症死亡的第四大原因。该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.