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Targeting the PI3K Signaling Axis

瞄准 PI3K 信号轴

基本信息

批准号：
8588487
负责人：
THOMAS M ROBERTS
金额：
$ 40.47万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588487
关键词：
1-Phosphatidylinositol 3-Kinase Address Adjuvant Adult Animals Biological Markers Blood - brain barrier anatomy Cancer Center Catalytic Domain Cell Culture Techniques Cell Cycle Regulation Clinic Clinical Clinical Trials Combined Modality Therapy Congenital Abnormality Data Dependence Development Disease Dose Drug Combinations Epidermal Growth Factor Receptor Event Genes Genetic Genetic screening method Genetically Engineered Mouse Genomics Glioblastoma Glioma Goals Grant Human In Vitro Individual Industry Institution Lead Malignant neoplasm of prostate Molecular Genetics Mutation Oncogenic PIK3CA gene PTEN gene Pathology Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phosphatidylinositide 3-Kinase Inhibitor Phosphotransferases Platelet-Derived Growth Factor Platelet-Derived Growth Factor alpha Receptor Primary Neoplasm Protein Isoforms Published Comment Radiation Radiation therapy Recurrence Relative (related person)Research Sampling Signal Transduction Staging Testing Therapeutic Therapeutic Intervention Translations Tumor Subtype Tumor Suppressor Proteins Tumor-Derived Work clinical material clinically relevant design driving force efficacy testing gain of function mutation genetic analysis improved inhibitor/antagonist kinase inhibitor loss of function mutation malignant breast neoplasm mouse model neurogenesis novel therapeutic intervention pre-clinical preclinical study research clinical testing research study response standard of care temozolomide therapeutic target tumor tumorigenesis

项目摘要

The phosphatidylinositol 3 kinase (P13K) signaling axis is aberrantly activated in the majority of adult highgrade gliomas. Activation in glioblastoma (GBM) occurs via one of four mechanisms: 1) Loss of function mutations in the PTEN tumor suppressor; 2) Amplification/gain of function mutations in the receptors for EGF or PDGF; 3) Activating mutations in the PIKSCA gene that encodes pi 10a, a catalytic subunit of PI3K, or; 4) mutations in the gene PIK3R1 that encodes one ofthe P13K regulatory subunits, p85a. A number of P13K inhibitors are in the early stages of clinical trials. One of these, BKM 120, is being developed by Novartis and has been shown to pass through the blood brain barrier, making it an excellent candidate for glioblastoma therapy. Project 2 will be centered on a trial of BKM in patients with recurrent glioblastoma. The broad goal of Project 2 is to use the data and clinical materials from patients on our BKM 120 trial- in concert with genetically defined mouse models - to address important unresolved questions involving PI3 kinase inhibitors as glioblastoma therapeutics. In addition to the key data on the impact of genetic modifiers on response to BKM120 (if any) coming from the human trial, cell culture and animal studies will address optimization of, and the potential benefits from, combination therapies using BKM 120 in concert with standard of care, as well as a number of rationally targeted therapies. Finally, great promise has been seen with inhibitors targeting a single catalytic isoform of PI3K. To prepare clinical testing of this new class of inhibitors, preclinical experiments will be carried out determining the relative importance ofthe individual P13K isoforms in disease driven by Pten loss.

磷脂酰肌醇3激酶（P13 K）信号转导轴在大多数成年高分化的乳腺癌中异常激活。神经胶质瘤胶质母细胞瘤（GBM）中的激活通过以下四种机制之一发生：1）功能丧失 PTEN肿瘤抑制基因突变; 2）EGF受体功能突变的扩增/获得 3）编码P110 a（PI 3 K的催化亚基）的PIKSCA基因中的激活突变，或; 4）编码P13 K调节亚基之一p85 a的基因PIK 3R 1突变。一批P13 K 这些抑制剂还处于临床试验的早期阶段。其中之一，BKM 120，正在开发的诺华和已被证明可以通过血脑屏障，使其成为胶质母细胞瘤的绝佳候选者疗法项目2将集中于BKM在复发性胶质母细胞瘤患者中的试验。广泛的目标项目2的第一步是使用我们BKM 120试验患者的数据和临床材料-与基因定义的小鼠模型-解决涉及PI 3激酶的重要未解决问题抑制剂作为胶质母细胞瘤治疗剂。除了有关遗传修饰剂对人的影响的关键数据之外，来自人体试验、细胞培养和动物研究的对BKM 120的反应（如有）将解决使用BKM 120与以下药物联合治疗的优化和潜在获益标准治疗，以及一些合理的靶向治疗。最后，与靶向PI 3 K的单一催化亚型的抑制剂。为了准备这类新药物的临床试验抑制剂，将进行临床前实验，以确定个体的相对重要性，疾病中的P13 K亚型由Pten损失驱动。