Evaluation of AZD9291 in Glioblastoma patients with activated EGFR

 描述（由申请人提供）：胶质母细胞瘤（GBM）是成人中最具侵袭性和最常见的原发性脑肿瘤之一。GBM患者的预后极差，目前的治疗（包括手术，放疗和化疗）未能将中位生存期延长至15个月以上。因此，迫切需要有效的GBM治疗。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GBM是异质性的，并且癌症基因组图谱（TCGA）计划已经确定了四种主要亚型。为了进一步了解GBM的分子异质性，我们最近在蛋白质组学水平上表征了一组20例患者来源的胶质母细胞瘤异种移植物（PDGX），并将其与相应的母体肿瘤的蛋白质组进行了比较。对20个PDGX的蛋白质组学分析的检查显示，其中7个具有由野生型EGFR扩增和EGFRvIII引起的活化的表皮生长因子受体（EGFR）。这些数据与在大比例GBM中观察到EGFR功能障碍的观察结果一致。此外，我们发现这些具有活化EGFR的特异性PDGX对其他几种蛋白质（包括HER 2）的磷酸化水平升高，这只强调了测试EGFR酪氨酸激酶抑制剂（EGFR-TKI）的重要性，如AZD 9291，因为它已被证明可以抑制EGFR和HER 2。AZD 9291的另一个关键特性是其良好的大脑渗透性。先前在GBM患者中进行的EGFR-TKI研究由于两个致命缺陷而失败：1）试验包括所有GBM患者，而不是 仅具有源自特定EGFR基因型的活化EGFR的那些，和2）EGFR-TKI具有差的脑渗透性。这两个缺陷都已从这项拟议的研究中删除。事实上，拟议的研究将具有活化EGFR的GBM患者细分为两组：1）活化EGFR为野生型的患者;和2）活化EGFR为EGFRvIII的患者。这种分离是有道理的，因为我们的数据显示，野生型和EGFRvIII的激活EGFR利用不同的信号通路。 本申请的UH 2部分（第1阶段）的重点是在具有激活EGFR的GBM临床前模型中测试AZD 9291，该激活EGFR源自具有基因扩增的野生型EGFR或EGFRvIII（Aim 1）。在拟议的临床前研究中的积极反应将导致UH 2部分的第二个目标，这将涉及1b期研究（目标2），以确定AZD 9291是否在安全剂量下到达肿瘤，接合靶点并抑制下游信号传导。Ib期研究的阳性应答将进入UH 3部分（第2阶段），该部分将评估AZD 9291在由对照组（标准治疗）和治疗组（AZD 9291+标准治疗）组成的IIa期试验（目的3）中的疗效。由于AZD 9291的独特性质，我们的分子定义的临床前模型，以及我们仅纳入那些表达靶点的GBM患者，拟议的研究将是第一个正确评估EGFR-TKI是否可以控制肿瘤由EGFR特异性异常驱动的患者的GBM生长的研究。为了成功完成拟议的研究，我们组建了一个由Kwatra（PI）、Lesser（PI）和吉尔伯特（脑肿瘤试验协作中心主任）组成的全面团队。

 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).