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。大量研究清楚地证实细胞周期激酶cdk4和cdk6在GBM发病过程中被激活。cdk4/6在GBM中激活的最常见机制是INK4位点（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已明确显示对活化的cdk4/6“成瘾”，因此这些蛋白代表了极有希望治疗GBM的分子靶点。最近，David James实验室（UCSF癌症中心）和Todd Waldman实验室（Georgetown医学院Lombardi癌症中心）的一项合作研究表明，cdk4/6的一种特异性药物抑制剂PD0332991在临床前模型中对阻止GBM的生长非常有效（Cancer Res 70:3228- 38,2010）。这项研究推动了首个用于检测GBM中cdk4/6特异性抑制剂的临床试验。这项以加州大学旧金山分校为基础的试验于2010年9月开始，迄今为止已有17名难治性复发性GBM患者入组。该资助申请旨在支持高质量的基础科学和转化研究，重点关注cdk4/6抑制作为GBM治疗靶点的效用。这项提议有三个目的。在Aim #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中抑制的关键靶点。在Aim #2中，我们将确定GBM对cdk4/6抑制的内在抗性和获得性抗性的机制。在Aim #3中，我们将评估PD0332991联合放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.