Targeting PTEN Null Tumors via Inhibition of the p110beta Isoform of PI3 Kinase

描述(由申请人提供)：IA类磷脂酰肌醇3激酶(PI3K)信号轴可能是人类癌症中最常见的激活途径。受体酪氨酸激酶(RTK)、G蛋白偶联受体(GPCRs)或RAS，IA类PI3Ks，由三种催化亚型组成，分别命名为p110？、p110？和p110？被激活，以产生主要的细胞内脂质信号，磷脂酰肌醇3，4，5-三磷酸(PIP3)，这是多种细胞过程中必不可少的。抑癌基因PTEN是一种脂质磷酸酶，可使PIP3去磷酸化，从而拮抗PI3K的作用，调节PI3K通路的活性。肿瘤中的通路激活最常见的是通过激活p110？异构体或通过缺失PTEN抑癌基因。重要的是，PI3K酶非常适合药物干预，使它们成为癌症治疗的有吸引力的靶点。事实上，有一些来自主要制药公司的PI3K抑制剂已经进入癌症治疗的临床试验，但这些抑制剂大多针对所有p110亚型，这可能会引起副作用，因为PI3K在正常生理中起着至关重要的作用。虽然异构体特异性抑制物正在进一步开发，但大多数是针对p110？(实体瘤)还是p110？(血液系统恶性肿瘤)。我们认为，制药公司犯了一个错误，未能开发出p110？特异性抑制剂。我们和其他人最近证明了由PTEN缺失驱动的肿瘤特异性地依赖于p110？不是p110？该项目的主要目标是产生p110？特异性抑制物，作为新的靶向疗法用于具有PTEN突变的各种癌症。为此，我们组建了一支为实现这一目标而优化的科学家团队。我们团队用于评估PI3K信号的独特试剂，再加上我们在蛋白质化学、X射线结晶学、药物化学和动物模型方面的专业知识，使我们能够有效地开发p110？在两年的时间内用于未来的临床试验。我们的具体目标是生成基于细胞的系统和遗传模型来确定p110的作用？在PTEN在不同组织类型中驱动的肿瘤发生中，检测p110？特异性抑制物，以纯化大量活性p110？用于酶分析和结晶学，并开展化学活动来设计和评估p110的新支架？使用细胞和动物模型和来自p110复合体的结构信息来抑制和优化这些支架中的2个？和一种抑制剂。 公共卫生相关性：说明该项目与公共健康的相关性：在多种类型的人类癌症中，抑癌基因PTEN在基因或表观遗传学上高度沉默。最近的数据表明，由PTEN缺失驱动的肿瘤依赖于一种称为p110？的特定PI3K亚型的活性。该项目旨在加快P110？这些药物可能会对许多癌症患者产生积极影响。

DESCRIPTION (provided by applicant): The class IA phosphatidylinositol 3 kinase (PI3K) signaling axis is perhaps the most frequently activated pathway in human cancer. In response to the activation of receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) or Ras, class IA PI3Ks, consisting of three catalytic isoforms termed p110?, p110? and p110?, are activated to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is essential for multiple cellular processes. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3, thereby antagonizing the actions of PI3K and regulating the PI3K pathway activity. Pathway activation in tumors is most commonly achieved through activating mutations in p110? isoform or via loss of the PTEN tumor suppressor. Importantly, PI3K enzymes are highly suited for pharmacological intervention, making them attractive targets for cancer therapy. In fact, there are a number of PI3K inhibitors from major pharmaceutical companies that have entered clinical trials for cancer treatment, but most of these inhibitors target all p110 isoforms, which may cause side effects arising from the essential roles of PI3K in normal physiology. While isoform specific inhibitors are being further developed, most of which are directed toward p110? (for solid tumors) or p110? (Hematological malignancies). We believe that the drug companies have blundered by failing to develop p110?-specific inhibitors. We and others have recently demonstrated that tumors driven by PTEN loss are specifically dependent of p110? not p110?. The broad goal of this project is to generate p110? -specific inhibitors for use as new, targeted therapeutics in diverse cancers featuring PTEN mutations. To this end we have assembled a team of scientists optimized to achieve this goal. Our team's unique reagents for assessing PI3K signaling, coupled with and our expertise in protein chemistry, X-ray crystallography, medicinal chemistry and animal models, position us to effectively develop p110? inhibitors over a two-year time period for future clinical trials. Our specific goals are to generate cell-based systems and genetic models to determine the role of p110? in tumorigenesis driven by PTEN in different tissue types and to test p110? -specific inhibitors, to purify large amounts of active p110? for enzyme assays and crystallography and to pursue a chemistry campaign to design and evaluate new scaffolds for p110? inhibition and optimize 2 of these scaffolds using both cell and animal models and structural information from a complex of p110? and an inhibitor. PUBLIC HEALTH RELEVANCE: Statement of the relevance of the project to public health: The PTEN tumor suppressor is genetically or epigenetically silenced at high frequency in may types of human cancer. Recent data suggests that tumors driven by PTEN loss are dependent on the activity of a particular isoform of PI3K termed p110?. This project is designed to speed development of p110? inhibitors and hence could have a positive impact on many cancer patients.