Cdk4/6 Inhibitor Therapy for Glioblastoma Multiforme

Cdk4/6 抑制剂治疗多形性胶质母细胞瘤

基本信息

批准号：
8840899
负责人：
Charles David James
金额：
$ 32.16万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840899
关键词：
Alkylating Agents Antibodies Applications Grants Avastin Basic Science Binding Biological Models Brain Neoplasms CDKN2A gene Cancer Center Cell Cycle Cell Cycle Arrest Cell Cycle Inhibition Cell Line Cells Clinical Clinical Trials Clinical Trials Design Collaborations Comprehensive Cancer Center Cyclin Gene DNA Damage DNA repair protein Data Disease Dose Enrollment Enzymes Epitopes Excision Family member Future Gene Amplification Generations Genes Genetic Glioblastoma Grant Growth Human In Vitro MGMT gene Malignant Neoplasms Modeling Molecular Target Mus Mutation Newly Diagnosed Pathogenesis Patients Pharmaceutical Preparations Phase II Clinical Trials Phosphotransferases Play Pre-Clinical Model Primary Brain Neoplasms Proteins Radiation therapy Recurrence Refractory Relative (related person)Research Research Personnel Resistance Role Sampling Signal Pathway System Techniques Testing Therapeutic Toxic effect Translating Translational Research Treatment Protocols Vascular Endothelial Growth Factors Xenograft procedure anticancer research base cancer therapy design effective therapy efficacy testing in vivo in vivo Model inhibitor/antagonist insight medical schools mouse model novel therapeutics prevent resistance mechanism response senescence standard of care temozolomide therapeutic target therapy resistant tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Gliobastoma multiforme (GBM) is the most common primary brain tumor and is incurable, with an average survival of 12-18 months. Numerous studies have clearly established that the cell cycle kinases cdk4 and cdk6 are activated during the pathogenesis of GBM. The most common mechanism for activation of cdk4/6 in GBM is homozygous deletion of the INK4 locus (containing the p16INK4a and p15INK4b genes). Less common mechanisms include amplification of the cdk4, cdk6, and cyclin genes themselves, and homozygous deletion of the p18INK4c gene. Since cdk4 and cdk6 are activated by these mechanisms in ~90% of GBMs and GBM has been clearly shown to be "addicted" to activated cdk4/6, these proteins represent an extremely promising molecular target for the treatment of GBM. Recently, a collaborative effort between David James' lab (UCSF Cancer Center) and Todd Waldman's lab (Lombardi Cancer Center, Georgetown Medical School) has demonstrated that PD0332991, a specific pharmacological inhibitor of cdk4/6, is remarkably effective in halting the growth of GBM in preclinical models (Cancer Res 70:3228-38, 2010). This study motivated the first clinical trial for testing a cdk4/6-specific inhibitor in GBM. Accrual for this UCSF-base trial was initiated in September, 2010, and 17 patients with treatment-refractory, recurrent GBM have thus far been enrolled. This grant application is designed to enable high quality basic science and translational research focusing on the utility of cdk4/6 inhibition as a therapeutic target for GBM. The proposal has three aims. In Aim #1, we will distinguish between the roles of cdk4 and cdk6 in GBM pathogenesis and determine which enzyme is the key target of inhibition by PD0332991 in GBM. In Aim #2, we will determine the mechanisms of intrinsic and acquired resistance to cdk4/6 inhibition in GBM. In Aim #3, we will evaluate the efficacy and toxicity of PD0332991 in combination with radiotherapy and temozolomide.

描述（由申请人提供）：多形胶质瘤（GBM）是最常见的原发性脑肿瘤，是无法治愈的，平均存活率为12-18个月。大量研究清楚地表明，在GBM发病机理期间，细胞周期激酶CDK4和CDK6被激活。 GBM中CDK4/6激活的最常见机制是Ink4基因座的纯合缺失（包含P16INK4A和P15INK4B基因）。不太常见的机制包括CDK4，CDK6和细胞周期蛋白基因本身的扩增以及p18Ink4c基因的纯合缺失。由于在〜90％的GBM中，这些机制激活了CDK4和CDK6，并且已清楚地证明了对活化的CDK4/6的GBM被“上瘾”，因此这些蛋白质代表了GBM治疗的极为有希望的分子靶标。最近，David James的实验室（UCSF癌症中心）与托德·沃尔德曼（Todd Waldman）的实验室（乔治敦医学院伦巴第癌中心）之间的合作努力表明，CDK4/6的特定药理抑制剂PD032991非常有效地停止临床前模型中的GBM（Cancer Res 70：3228-38，2010）。这项研究促使第一次测试GBM中CDK4/6特异性抑制剂的临床试验。这项UCSF基本试验的应计于2010年9月启动，迄今为止，已纳入了17例治疗难治性的患者。该赠款应用程序旨在使高质量的基础科学和翻译研究重点介绍CDK4/6抑制作用作为GBM的治疗靶点。该提案有三个目标。在AIM＃1中，我们将区分CDK4和CDK6在GBM发病机理中的作用，并确定哪种酶是PD0332991在GBM中抑制的关键靶标。在AIM＃2中，我们将确定GBM中对CDK4/6抑制的固有和获得性的机制。在AIM＃3中，我们将评估PD032991与放射疗法和替莫唑胺的功效和毒性。