Evaluation of AZD9291 in Glioblastoma patients with activated EGFR

 描述(申请人提供)：胶质母细胞瘤(GBM)是成人最具侵袭性和最常见的原发脑肿瘤之一。GBM患者的预后非常差，目前的治疗(包括手术、放射治疗和化疗)未能延长15个月以上的中位生存期。因此，迫切需要一种有效的GBM治疗方法。为了实现这一目标，我们需要了解驱动GBM的分子机制。最近的研究表明，基底膜是异质性的，癌症基因组图谱(TCGA)程序已经确定了四种主要的亚型。为了进一步了解GBM的分子异质性，我们最近从蛋白质组水平鉴定了20例患者来源的胶质母细胞瘤异种移植瘤(PDGX)，并将每个移植瘤与其相应亲本肿瘤的蛋白质组进行了比较。对20个PDGX的蛋白质组图谱的研究表明，其中7个具有激活的表皮生长因子受体(EGFR)，来自野生型EGFR扩增和EGFRvIII。这样的数据与观察到的EGFR功能障碍在很大比例的GBM中是一致的。此外，我们发现这些激活了EGFR的特定PDGX增加了包括HER2在内的其他几种蛋白质的磷酸化，这只强调了测试EGFR酪氨酸激酶抑制剂(EGFR-TKI)的重要性，例如AZD9291，因为它已经被证明可以抑制EGFR和HER2。AZD9291的另一个关键特征是其良好的大脑穿透性。之前对GBM患者进行的EGFR-TKI研究因两个致命缺陷而失败：1)试验包括所有GBM患者，而不是 只有那些激活的EGFR源自特定的EGFR基因，以及2)EGFR-TKI的大脑渗透性很差。这两个缺陷都已从这项拟议的研究中删除。事实上，这项拟议的研究将EGFR激活的GBM患者细分为两组：1)EGFR激活的患者为野生型；2)EGFR激活的患者为EGFRvIII。这种分离是合理的，因为我们的数据表明，野生型和EGFRvIII激活的EGFR使用不同的信号通路。本申请的UH2部分(阶段1)的重点是在GBM的临床前模型中测试AZD9291，其中激活的EGFR来自野生型EGFR和基因扩增的EGFR或EGFRvIII(目标1)。拟议的临床前研究中的积极反应将导致UH2部分的第二个目标，这将涉及1b阶段研究(目标2)，以确定AZD9291在安全剂量下是否到达肿瘤，与靶点结合，并抑制下游信号转导。1b期研究的积极反应将导致UH3部分(第2阶段)，该部分将评估AZD9291在2a期试验(AIM 3)中的疗效，该试验包括对照(护理标准)和接受治疗的ARM(AZD9291加护理标准)。由于AZD9291‘S的独特性质、我们的分子定义的临床前模型以及我们只纳入表达靶点的基底膜患者，拟议的研究将首次正确评估EGFR-TKI是否可以控制其肿瘤由EGFR特定异常驱动的患者的基底膜生长。为了成功地完成这项拟议的研究，我们组建了一个全面的团队，由Kwatra博士(PI)、Lesser(PI)和Gilbert(脑瘤试验合作中心主任)组成。

 DESCRIPTION (provided by applicant): Glioblastoma (GBM) is among the most aggressive and common primary brain tumors in adults. GBM patients have an extremely poor prognosis, and current treatments (including surgery, radiation therapy, and chemotherapy) have failed to extend median survival beyond 15 months. Therefore, the need for an effective GBM therapy is urgent. To achieve this goal, we need to understand the molecular machinery that drives GBM. Recent studies indicate that GBMs are heterogeneous, and four major subtypes have been identified by The Cancer Genome Atlas (TCGA) program. To further understand the molecular heterogeneity of GBM, we recently characterized a panel of 20 patient-derived glioblastoma xenografts (PDGX) at the proteomic level and compared each with the proteome of its corresponding parent tumor. An examination of the proteomic profiling of 20 PDGX revealed that 7 of them have activated epidermal growth factor receptor (EGFR) arising from both wild-type EGFR amplification and EGFRvIII. Such data is consistent with the observation that EGFR dysfunction is seen in a large proportion of GBMs. Furthermore, we found these specific PDGX with activated EGFR have elevated phosphorylation of several other proteins, including HER2, which only underscores the importance of testing an EGFR tyrosine kinase inhibitor (EGFR-TKI), such as AZD9291, since it has been proven to inhibit both EGFR and HER2. Another key characteristic of AZD9291 is its good brain penetration. Previous studies of EGFR-TKI in GBM patients have failed because of two fatal flaws: 1) the trial included all GBM patients, instead of just those with activated EGFR originating from a specific EGFR genotype, and 2) the EGFR-TKI had poor brain penetration. Both flaws have been removed from this proposed study. In fact, the proposed study will subdivide GBM patients with activated EGFR into two groups: 1) patients whose activated EGFR is wild-type; and 2) patients whose activated EGFR is EGFRvIII. This segregation is warranted because our data show that activated EGFR from wild-type and EGFRvIII utilize different signaling pathways. The focus of the UH2 part (stage 1) of this application is to test AZD9291 in preclinical models of GBM with activated EGFR originating from either wild-type EGFR with gene amplification or EGFRvIII (Aim 1). A positive response in the proposed preclinical studies will lead to the second goal of the UH2 part, which will involve phase 1b studies (Aim 2) to determine whether AZD9291, at safe doses, reaches the tumor, engages the target, and inhibits downstream signaling. A positive response from phase 1b studies will lead to UH3 part (stage 2), which will assess the efficacy of AZD9291 in phase 2a trials (Aim 3) consisting of control (standard of care) and treated arm (AZD9291 plus standard of care). Because of AZD9291's unique properties, our molecularly-defined preclinical models, and our inclusion of only those GBM patients expressing the target, the proposed studies will be the first to properly evaluate whether or not an EGFR-TKI can control GBM growth in patients whose tumor is driven by specific abnormalities in EGFR. To successfully complete the proposed study, we have assembled a well-rounded team consisting of Drs. Kwatra (PI), Lesser (PI), and Gilbert (director of the Brain Tumor Trials Collaborative).