Cdk4/6 Inhibitor Therapy for Glioblastoma Multiforme

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，是无法治愈的，平均生存12-18个月。大量研究表明，细胞周期蛋白激酶CDK4和CDK6在GBM的发病过程中被激活。CDK4/6在GBM中最常见的激活机制是INK4基因的纯合缺失(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，这些蛋白是治疗GBM的一个非常有前途的分子靶点。最近，大卫·詹姆斯的实验室(加州大学旧金山分校癌症中心)和托德·沃尔德曼的实验室(乔治敦医学院隆巴迪癌症中心)的一项合作努力证明，CDK4/6的特定药理抑制剂PD0332991在临床前模型中显著有效地阻止基底膜的生长(癌症资源70：3228-38,2010)。这项研究推动了在GBM中测试CDK4/6特异性抑制剂的第一次临床试验。这项基于加州大学旧金山分校的试验于2010年9月启动，迄今已有17名治疗难治、复发的GBM患者入选。这项赠款申请旨在实现高质量的基础科学和转化性研究，重点是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抑制GBM的关键靶点。在目标2中，我们将确定GBM对CDK4/6抑制的内在和获得性耐药的机制。在第三个目标中，我们将评估PD0332991联合放射治疗和替莫唑胺的疗效和毒性。

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.