The role of PTEN feedback mechanism in cancer

项目摘要/摘要 在我们对PTEN如何维持肿瘤抑制作用的理解上仍然存在一个根本的差距 生理水平，以及这一水平在癌症中如何被解除调控，从而导致人类的PTEN生物学 癌症在很大程度上令人费解。我们的长期目标是填补这一空白，从而使 治疗癌症的新靶向疗法。此应用程序特定目标是识别新的 用于预防和治疗目的的PTEN信号的调节机制。我们的中心假设是 PTEN是由反馈机制自动调节的，这种新颖的PTEN集成电路起到了 在肿瘤抑制中发挥重要作用，并可能为癌症治疗提供令人兴奋的新选择。这一假设 是根据申请人实验室提供的初步数据制定的。其基本原理是 这项拟议的研究是，一旦我们知道PTEN在癌症中的剂量是如何调节的，PTEN的活性 调节剂很可能被药理学地操纵以恢复PTEN的表达，从而导致新的和 创新预防和治疗方法。在强劲的初步数据的指导下，我们将检验我们的假设 通过追求三个特定的目标：1)确定在基因敲除小鼠中，一种新的生理性去泛素酶的作用 (DUB)PTEN在肿瘤发生中的作用；2)确定DUB和DUB之间串扰的分子基础 PTEN-PI3K-AKT网络；3)评估药物诱导的PTEN修复的益处 DUB的激活是一种很有前途的治疗选择。在第一个目标下，一系列PTEN特异性配音 已经创建并被申请者发现可行的基因敲除老鼠模型将是 以肿瘤发生为特征的。在第二个目标下，申请人对PTEN特异性复制的识别为 PI3K-AKT途径的一个新的、必不可少的下游靶点将被进一步验证，以探索可能的联系 DUB和PTEN-PI3K-AKT网络在肿瘤发生中的作用。在第三个目标下，进行临床前评估 一种已经证实的激活PTEN的药物DUB和与PI3K或PARP抑制剂的联合治疗将是 在癌症的遗传模型中进行。这种方法是创新的，因为它探索了PTEN的调节 一种新的、关键的PTEN反馈机制作为令人兴奋的新疗法的来源的剂量和活性 机会，申请人相信由此产生的发现将开辟治疗的新天地 研究。拟议的工作也具有重大意义，因为预计它将垂直推进和扩大 了解PTEN整合的信号网络在许多人类癌症中是如何被解除调控的。 最终，旨在促进PTEN反馈机制的治疗干预可能被证明是有用的 在阻止癌症发展方面，因此拥有巨大的预防和治疗前景。

Project Summary/Abstract There remains a fundamental gap in our understanding of how PTEN maintains a tumor-suppressive physiological level, and how this level becomes deregulated in cancer which renders PTEN biology in human cancer largely incomprehensible. Our long-term goal is to fill that gap, and thereby enable the development of novel targeted therapeutics for treating cancer. The specific objective of this application is to identify novel regulatory mechanisms of PTEN signaling for preventative and therapeutic purposes. Our central hypothesis is that PTEN is auto-regulated by feedback mechanism, and that this novel PTEN “integrated circuit” plays an important role in tumor suppression and could offer exciting new options for cancer therapy. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that once we know how PTEN dosage is regulated in cancer, the activity of PTEN modulators can likely be manipulated pharmacologically to restore PTEN expression, resulting in new and innovate approaches to prevention and therapy. Guided by strong preliminary data, we will test our hypothesis by pursuing three specific aims: 1) To define, in knockout mice, the role of a novel physiological deubiquitinase (DUB) for PTEN in tumorigenesis; 2) To determine the molecular basis of the crosstalk between the DUB and PTEN-PI3K-AKT networks; and 3) To assess the benefit of PTEN restoration induced by pharmacological activation of DUB as a promising therapeutic option. Under the first aim, a series of PTEN specific DUB knockout mouse models, which have been already created and found feasible by the applicant, will be characterized for tumorigenesis. Under the second aim, the applicant's identification of PTEN specific DUB as a novel, essential downstream target of the PI3K-AKT pathway will be further verified to explore a possible link between the DUB and PTEN-PI3K-AKT networks in tumorigenesis. Under the third aim, a preclinical evaluation of an already proven agent activating PTEN DUB and combined therapy with inhibitors of PI3K or PARP will be undertaken in genetic models of cancer. This approach is innovative in that it explores the regulation of PTEN dosage and activity by a novel, critical PTEN feedback mechanism as a source of exciting new therapeutic opportunities, and the applicant is confident the resulting findings will open new horizons for therapeutic research. The proposed work is also significant in that it is expected to vertically advance and expand understanding of how PTEN-integrated signaling networks are deregulated in many human cancers. Ultimately, therapeutic interventions designed to advance the PTEN feedback mechanism could prove useful in blocking cancer development, and so hold great preventative and therapeutic promise.