Cdk4/6 Inhibitor Therapy for Glioblastoma Multiforme

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。许多研究已经清楚地证实，细胞周期激酶cdk 4和cdk 6在GBM的发病过程中被激活。GBM中cdk 4/6激活的最常见机制是INK 4基因座（包含p16 INK 4a和p15 INK 4 b基因）的纯合缺失。不太常见的机制包括cdk 4、cdk 6和细胞周期蛋白基因本身的扩增，以及p18 INK 4c基因的纯合缺失。由于cdk 4和cdk 6在约90%的GBM中被这些机制激活，并且GBM已清楚地显示出对激活的cdk 4/6“上瘾”，因此这些蛋白质代表了用于治疗GBM的极有希望的分子靶标。最近，大卫詹姆斯的实验室（UCSF癌症中心）和托德沃尔德曼的实验室（Lombardi癌症中心，乔治敦医学院）之间的合作努力已经证明，PD 0332991（cdk 4/6的特异性药理学抑制剂）在临床前模型中显著有效地停止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cdk 4/6特异性抑制剂的临床试验。这项基于UCSF的试验于2010年9月开始招募，迄今为止已招募了17例治疗难治性复发性GBM患者。该资助申请旨在实现高质量的基础科学和转化研究，重点是cdk 4/6抑制作为GBM治疗靶点的实用性。该提案有三个目标。在目标#1中，我们将区分cdk 4和cdk 6在GBM发病机制中的作用，并确定哪种酶是GBM中PD 0332991抑制的关键靶标。在目标#2中，我们将确定GBM中对cdk 4/6抑制的内在和获得性抗性的机制。在目标#3中，我们将评估PD 0332991与放射疗法和替莫唑胺组合的疗效和毒性。

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.