The role of PTEN feedback mechanism in cancer

PTEN反馈机制在癌症中的作用

• 批准号: 9314466
• 负责人: Min Sup Song
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314466
• 关键词: Alleles; Biology; Cancer Biology; Clinic; Data; Degenerative Disorder; Development; Disease; Feedback; Genetic; Genetic Models for Cancer; Genomics; Goals; Human; Knockout Mice; Knowledge; Laboratories; Link; Malignant Neoplasms; Medical; Metabolic syndrome; Metabolism; Mission; Modeling; Molecular; Mus; Mutate; Outcome; PTEN gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Pharmacology; Physiological; Play; Predisposition; Prevention approach; Prevention therapy; Protein Dephosphorylation; Proto-Oncogene Proteins c-akt; Public Health; Quality of life; Regulation; Repression; Research; Research Personnel; Resveratrol; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Source; TSC2 gene; Testing; Therapeutic; Therapeutic Human Experimentation; Therapeutic Intervention; Tumor Suppression; Tumor Suppressor Genes; United States National Institutes of Health; Up-Regulation; Variant; Work; base; cancer therapy; cell growth; clinical application; design; dosage; genetic analysis; improved; improved outcome; inhibitor/antagonist; innovation; mTOR Signaling Pathway; mouse model; new therapeutic target; novel; novel therapeutics; patient stratification; phosphoinositide-3,4,5-triphosphate; pre-clinical; preclinical evaluation; protein expression; restoration; therapy design; tool; tumor; tumor initiation; tumorigenesis

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.

项目总结/摘要 在我们对PTEN如何维持肿瘤抑制作用的理解中，仍然存在着根本性的差距。 生理水平，以及该水平如何在癌症中变得失调，这使得人类中的PTEN生物学 癌症很难理解。我们的长期目标是填补这一空白，从而促进 用于治疗癌症的新型靶向治疗剂。本申请的具体目的是鉴定新的 用于预防和治疗目的的PTEN信号传导的调节机制。我们的核心假设是 PTEN是通过反馈机制自动调节的，并且这种新型的PTEN“集成电路”发挥了 在肿瘤抑制中起重要作用，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。的理由 这项研究的目的是，一旦我们知道了癌症中PTEN的剂量是如何调节的， 调节剂可能会被操纵，以恢复PTEN表达，导致新的， 创新预防和治疗方法。在强有力的初步数据的指导下，我们将测试我们的假设 通过追求三个具体目标：1）在基因敲除小鼠中确定一种新的生理性去泛素化酶的作用， (DUB)2）确定DUB和PTEN之间串扰的分子基础， PTEN-PI 3 K-AKT网络;和3）评估通过药物治疗诱导的PTEN恢复的益处。 激活DUB作为一个有前途的治疗选择。在第一个目标下，一系列PTEN特异性DUB 申请人已经建立并发现可行的基因敲除小鼠模型将被 以肿瘤发生为特征。在第二个目标下，申请人将PTEN特异性DUB鉴定为 PI 3 K-AKT通路的一个新的、重要的下游靶点将被进一步验证，以探索可能的联系。 DUB和PTEN-PI 3 K-AKT网络在肿瘤发生中的作用。在第三个目标下，临床前评价 已经证实的激活PTEN DUB的药物和与PI 3 K或PARP抑制剂的联合治疗将是 在癌症遗传模型中进行。这种方法是创新的，因为它探索了PTEN的调节 剂量和活性的一种新的，关键的PTEN反馈机制作为一个令人兴奋的新的治疗来源， 机会，申请人相信由此产生的发现将为治疗开辟新的视野。 research.拟议工作的意义还在于，有望纵向推进和扩大 了解PTEN整合的信号网络如何在许多人类癌症中失调。 最终，旨在促进PTEN反馈机制的治疗干预可能会被证明是有用的 阻止癌症发展，因此具有很大的预防和治疗前景。