Phosphatidylinositol 3-kinase and prevention of pancreatic cancer

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10%。 超过5%。迫切需要对这种疾病采取更好的预防和治疗战略。不像大多数其他 作为实体恶性肿瘤，PDA在遗传上惊人地同质。绝大多数（>90%）人类PDA 含有一个独特的基因特征：它们具有Kras原癌基因的激活突变。的关键作用 Kras激活在这种恶性肿瘤的发展中的作用得到了研究的支持，研究表明， 胰腺细胞中激活的Kras突变体发展成癌前和恶性肿瘤的全谱 常见于胰腺癌患者。该提案解决了一个重要的研究问题， 高翻译值：下调磷脂酰肌醇3-激酶（PI 3 K）p110能阻止 发展或阻断致癌Kras诱导的胰腺癌的进展？Aim 1使用分子 和细胞研究，以获得机制洞察PI 3 K p110调节和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 p110 <$的基因切除， 测试p110 a是否是胰腺癌可行的治疗靶点。Aim 3使用药理学方法， 研究PI 3 K的化学抑制是否是预防PDA发展的安全方法。 Kras诱导肿瘤。这项研究的结果对现有PI 3 K的测试具有明显的临床意义 抑制剂和用于开发这类新化合物。成功完成我们的动物 研究应导致调查天然和合成PI 3 K抑制剂作为化学预防干预 用于人类胰腺癌。

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) p110¿ 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 p110¿ 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 p110¿ 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.