Defining PI3K p110alpha as a therapeutic target in pancreatic cancer

将 PI3K p110alpha 定义为胰腺癌的治疗靶点

• 批准号: 8468032
• 负责人: Eileen S Carpenter
• 金额: $ 3.08万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-02 至 2016-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468032
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Adjuvant Therapy; Binding; Breeding; Cancer Etiology; Cancer Model; Cancer Patient; Carcinoma; Catalytic Domain; Characteristics; Clinical; Clinical Research; Data; Dependence; Development; Disease; Drug Design; Drug Targeting; Enzymes; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Guanosine Triphosphate; Heterogeneity; Hot Spot; Human; Knock-in Mouse; Laboratories; Left; Legitimacy; Lipids; Lung; MAPK14 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular; Mus; Mutation; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Proteins; Radiation therapy; Receptor Protein-Tyrosine Kinases; Relative (related person); Reporting; Resistance; Role; Second Messenger Systems; Signal Transduction; Staging; System; Testing; Tetracyclines; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; base; cancer therapy; chemotherapy; gain of function; in vivo; inhibitor/antagonist; kinase inhibitor; mouse model; mutant; novel; pancreatic neoplasm; pancreatic tumorigenesis; prevent; ras Proteins; research study; second messenger; small molecule; therapeutic target; tumor; tumor growth; tumorigenesis; tumorigenic; tyrosine receptor

DESCRIPTION (provided by applicant): New drug targets are urgently needed for the development of primary and adjuvant therapies for pancreatic ductal adenocarcinoma. Nearly all pancreatic ductal adenocarcinomas are caused by activating mutations in the Kras gene. Pharmacological inhibition of Kras has been unsuccessful. However, oncogenic Kras activates several enzymes that are more easily targeted with small molecule inhibitors that can be developed as drugs. Our proposed study focuses on one such enzyme, namely phosphatidylinositol 3-kinase (PI3K) p110¿. Our preliminary studies showed that ablation of the p110¿ gene in the mouse pancreas completely prevented the development of pancreatic cancer caused by oncogenic Kras without causing any detectable harmful effects. These results suggest the exciting possibility that p110¿ might be a legitimate drug target for the treatment of pancreatic cancer. This proposal will extend upon these results through the use of novel inducible mouse models that have high translational relevance for the development of pancreatic cancer treatment. First, the dependence of already-formed tumors on p110¿ will be investigated using genetically engineered mice whose p110¿ expression can be modulated at will. This scenario will closely model the clinical situation where pancreatic cancer patients are treated with PI3K inhibitors. Second, the necessity of catalytic activity of p110¿ in pancreatic oncogenesis will be determined using mice expressing a kinase-dead form of p110¿, and the sufficiency of catalytic activity will be tested using mice expressing a constitutively active formof the kinase. Since these mouse models are also inducible, their requirement for tumor maintenance will also be investigated as a secondary study. Finally, the importance of the physical interaction between Ras and p110¿ will be investigated using knock-in mice expressing a mutant p110¿ that is incapable of binding to Ras. Results from these studies will not only validate the legitimacy of p110¿ as a suitable drug target for pancreatic cancer, but also elucidate the mechanistic role of p110¿ in pancreatic oncognesis so as to provide a better understanding of this therapeutic target.

描述（申请人提供）： 胰腺导管腺癌的主要治疗和辅助治疗迫切需要新的药物靶标，但几乎所有胰腺导管腺癌都是由激活 Kras 基因突变引起的。 ，致癌性 Kras 会激活几种酶，这些酶更容易被小分子抑制剂靶向，这些小分子抑制剂可以开发为药物。酶，即磷脂酰肌醇 3-激酶 (PI3K) p110¿我们的初步研究表明 p110 的消融小鼠胰腺中的基因完全阻止了致癌性 Kras 引起的胰腺癌的发展，而不会造成任何可检测到的有害影响。这些结果表明 p110 的令人兴奋的可能性。该提案将通过使用与胰腺癌治疗的发展具有高度转化相关性的新型诱导小鼠模型来扩展这些结果。在 p110¿将使用 p110 的基因工程小鼠进行研究这种情况将密切模拟胰腺癌患者接受 PI3K 抑制剂治疗的临床情况。 其次，p110 催化活性的必要性。将使用表达激酶死亡形式的 p110 的小鼠来确定胰腺肿瘤发生中的作用，并且将使用表达激酶的组成型活性形式的小鼠来测试催化活性的充分性，因为这些小鼠模型也是可诱导的，所以还将研究它们对肿瘤维持的要求最后，物理的重要性。 Ras 和 p110 之间的相互作用¿将使用表达突变体 p110 的敲入小鼠进行研究这些研究的结果不仅会验证 p110 的合法性。作为胰腺癌的合适药物靶点，同时也阐明了 p110 的机制作用¿胰腺肿瘤的研究，以便更好地了解这一治疗靶点。