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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：
8658297
负责人：
Charles David James
金额：
$ 31.2万
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658297
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 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（申请人提供）：多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，无法治愈，平均生存期为 12-18 个月。大量研究已明确证实细胞周期激酶 cdk4 和 cdk6 在 GBM 发病过程中被激活。 GBM 中 cdk4/6 激活的最常见机制是 INK4 基因座（包含 p16INK4a 和 p15INK4b 基因）的纯合缺失。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 cdk4 和 cdk6 在约 90% 的 GBM 中被这些机制激活，并且 GBM 已被清楚地证明对激活的 cdk4/6“上瘾”，因此这些蛋白质代表了治疗 GBM 的极其有前途的分子靶点。最近，David James 实验室（加州大学旧金山分校癌症中心）和 Todd Waldman 实验室（乔治城医学院隆巴迪癌症中心）之间的合作证明，PD0332991（一种 cdk4/6 的特定药理学抑制剂）在临床前模型中可非常有效地阻止 GBM 的生长（Cancer Res 70:3228-38, 2010）。这项研究激发了第一个在 GBM 中测试 cdk4/6 特异性抑制剂的临床试验。这项以 UCSF 为基地的试验于 2010 年 9 月开始招募，迄今为止已招募了 17 名难治性复发性 GBM 患者。该拨款申请旨在实现高质量的基础科学和转化研究，重点关注 cdk4/6 抑制作为 GBM 治疗靶点的用途。该提案有三个目标。在目标#1中，我们将区分 cdk4 和 cdk6 在 GBM 发病机制中的作用，并确定哪种酶是 PD0332991 在 GBM 中抑制的关键靶标。在目标 #2 中，我们将确定 GBM 中对 cdk4/6 抑制的内在和获得性耐药机制。在目标#3中，我们将评估 PD0332991 与放疗和替莫唑胺联合使用的疗效和毒性。