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（PI 3 K）信号传导轴可能是人类癌症中最常激活的途径。作为对受体酪氨酸激酶（RTK）、G蛋白偶联受体（GPCR）或Ras激活的响应，IA类PI 3 K由三种催化亚型（称为p110？）组成，p110？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（PIP 3），其对于多个细胞过程是必需的。肿瘤抑制因子PTEN（一种脂质磷酸酶）使PIP 3去磷酸化，从而拮抗PI 3 K的作用并调节PI 3 K途径活性。肿瘤中的通路激活最常见的是通过激活p110？同种型或通过PTEN肿瘤抑制因子的缺失。重要的是，PI 3 K酶非常适合药物干预，使其成为癌症治疗的有吸引力的靶点。事实上，有许多来自主要制药公司的PI 3 K抑制剂已进入癌症治疗的临床试验，但这些抑制剂中的大多数针对所有p110亚型，这可能会导致PI 3 K在正常生理学中的重要作用引起的副作用。虽然亚型特异性抑制剂正在进一步开发，其中大部分是针对p110？(for实体瘤）或p110？（血液恶性肿瘤）。我们认为制药公司没有开发出p110？特异性抑制剂我们和其他人最近已经证明，由PTEN丢失驱动的肿瘤特异性依赖于p110？不是p110。这个项目的主要目标是产生p110？- 在以PTEN突变为特征的多种癌症中用作新的靶向治疗剂的特异性抑制剂。为此，我们组建了一个科学家团队，以实现这一目标。我们的团队的独特试剂，用于评估PI 3 K信号，再加上我们在蛋白质化学，X射线晶体学，药物化学和动物模型的专业知识，使我们能够有效地开发p110？在未来的临床试验中，我们将在两年的时间内研究抑制剂。我们的具体目标是产生基于细胞的系统和遗传模型，以确定p110的作用？在不同组织类型中由PTEN驱动的肿瘤发生中，并测试p110？- 特异性抑制剂，以纯化大量的活性p110？用于酶分析和晶体学，并进行化学活动，以设计和评估p110的新支架？抑制和优化2这些支架使用细胞和动物模型和结构信息从复杂的p110？和抑制剂。 公共卫生相关性：该项目与公共卫生相关性的声明：PTEN肿瘤抑制基因在多种类型的人类癌症中高频率地遗传或表观遗传沉默。最近的数据表明，由PTEN丢失驱动的肿瘤依赖于PI 3 K的一种特殊亚型p110？的活性。该项目旨在加快p110的开发。抑制剂，因此可能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.