Small molecule inhibitors with a therapeutic window for EGFR signaling variants in glioblastoma

针对胶质母细胞瘤中 EGFR 信号变异具有治疗窗口的小分子抑制剂

• 批准号: 10306230
• 负责人: MICHAEL J ECK
• 金额: $ 19.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306230
• 关键词: Adult; Basic Science; Binding; Biochemical; Biological Assay; Brain; Clinical; Clinical Trials; Collaborations; Dana-Farber Cancer Institute; Dimerization; Disease; Dose; Dose-Limiting; Drug Kinetics; EGF gene; EGFR gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exhibits; Failure; Gastrointestinal tract structure; Generations; Genetic; Genetic Models; Genetically Engineered Mouse; Genomics; Glioblastoma; Grant; Image; Industry; Knock-out; Lead; Letters; Ligands; Malignant neoplasm of lung; Mass Spectrum Analysis; Maximum Tolerated Dose; Molecular; Molecular Conformation; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Operative Surgical Procedures; Oral; Patients; Penetrance; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phosphotransferases; Plasma; Property; Receptor Inhibition; Receptor Signaling; Recurrence; Resistance; Safety; Signal Transduction; Skin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; Testing; Therapeutic; Tissues; Toxic effect; Tyrosine Kinase Domain; Tyrosine Kinase Inhibitor; Variant; Work; Xenograft Model; base; clinical development; clinical effect; clinical material; clinical translation; dimer; drug development; effective therapy; efficacy study; epidermal growth factor receptor VIII; experience; first-in-human; genetic inhibitor; inhibitor/antagonist; monomer; mutant; new therapeutic target; novel; pre-clinical; programs; receptor; single cell sequencing; small molecule; small molecule inhibitor; stem; tumor; tumor heterogeneity

Project Summary The epidermal growth factor receptor (EGFR) gene is mutated or amplified in over half of GBMs, and its mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed tyrosine kinase inhibitors (TKIs) have failed to show efficacy in this disease and these failures cannot be attributed strictly to poor brain penetrance. We posit that the failure to date of EGFR TKIs for GBM reflects lack of a therapeutic window. A lesson learned from application of EGFR inhibitors in non-small cell lung cancer (NSCLC) is that mutant-selectivity is absolutely required. Without selectivity, systemic inhibition of wild-type (WT) EGFR signaling is the dose-limiting toxicity. In NSCLC, activating mutations in the tyrosine kinase domain confer enhanced sensitivity to certain EGFR TKIs relative to WT EGFR, allowing true mutant-selective inhibition. The EGFR genetic aberrations in glioblastoma (GBM) create constitutive, ligand-independent signaling via signal generating domains that are almost exclusively WT in structure. Our objective is to create EGFR TKIs with a therapeutic window for aberrant EGFR signaling in GBM. We have two specific aims. Aim 1, is to test the hypothesis that an EGFR TKI with an allosteric mechanism of action will selectively block ligand-independent EGFR signaling in GBM while sparing ligand-activated EGFR systemically, thereby providing a therapeutic window that allows effective treatment of EGFR-driven GBMs. In preliminary studies, we have developed small-molecule allosteric inhibitors that potently inhibit WT EGFR (IC50 < 100 nM in biochemical assays) and have a good oral mouse PK profile and are brain-penetrant. Guided by efficacy studies in patient-derived GBM neurosphere and xenograft models, we expect to identify a compound suitable for clinical development in the first grant year, to enable clinical translation in the out years. Aim 2, exploits CM93, a novel third generation EGFR TKI that is highly brain-penetrant – so much so that it actually displays a positive brain/plasma ratio. We will test the hypothesis that CM93 can provide a de facto “tissue-based” therapeutic window allowing effective inhibition of EGFR in the tumor with relative sparing of the receptor systemically. Towards this end, we will conduct a first-in-human, phase 1, dose-escalation and dose-expansion study, as well as a surgical “window of opportunity” study to determine the maximum tolerated dose, evaluate the safety, pharmacokinetics, pharmacodynamics and clinical effects of orally administered CM93 in subjects with recurrent glioblastoma characterized by EGFR mutation or amplification. Studies on clinical materials will be facilitated by our Pharmacological and Genomics Imaging Core (PGIC). The PGIC will allow us to quantify intra-tumoral accumulation of CM93 using MALDI mass spectrometry imaging and to define the impact of CM93 treatment on tumor heterogeneity using single cell sequencing. Collectively, these studies promise to yield new targeted therapeutics for EGFR-driven GBMs and provide a molecular understanding of determinants of sensitivity and resistance to these agents.

项目摘要 表皮生长因子受体（EGFR）基因突变或扩增超过一半的GBM，其 突变和局部扩增与更侵袭性的病程相关。然而，EGFR导向的 酪氨酸激酶抑制剂（TKI）未能在这种疾病中显示出疗效，并且这些失败不能被认为是有效的。 严格归因于大脑的不清醒。我们认为，迄今为止EGFR TKI治疗GBM的失败反映了缺乏 一个治疗窗口。EGFR抑制剂治疗非小细胞肺癌的经验教训 （NSCLC）是绝对需要的。无选择性，系统抑制野生型 (WT)EGFR信号传导是剂量限制性毒性。在NSCLC中，酪氨酸激酶结构域中的激活突变 相对于WT EGFR，赋予对某些EGFR TKI的敏感性增强， 抑制作用胶质母细胞瘤（GBM）中的EGFR基因畸变产生了组成性的、配体非依赖性的 通过在结构上几乎完全是WT的信号产生结构域进行信号传导。我们的目标是创造 EGFR TKI在GBM中具有异常EGFR信号传导的治疗窗口。我们有两个具体目标。 目的1是检验具有变构作用机制的EGFR TKI将选择性地 阻断GBM中配体非依赖性EGFR信号传导，同时全身性保留配体激活的EGFR， 提供允许有效治疗EGFR驱动的GBM的治疗窗。在初步研究中， 我们已经开发了小分子变构抑制剂，其有效地抑制WT EGFR（IC 50 < 100 nM， 生物化学测定），并且具有良好的口服小鼠PK特征并且是脑渗透性的。以功效为导向 在患者来源的GBM神经球和异种移植模型中的研究中，我们期望鉴定出适合的化合物 在第一个资助年度进行临床开发，以便在接下来的几年里进行临床翻译。 目的2，利用CM 93，一种新型的第三代EGFR TKI，具有高度的脑渗透性-如此之多， 它实际上显示了一个积极的脑/血浆比例。我们将测试CM 93可以提供一个 事实上的“基于组织的”治疗窗口允许有效抑制肿瘤中的EGFR， 受体的系统性。为此，我们将进行首次人体试验，1期，剂量递增， 剂量扩展研究，以及手术“机会窗”研究，以确定最大耐受剂量 剂量，评价口服给药的安全性、药代动力学、药效学和临床效果 CM 93在以EGFR突变或扩增为特征的复发性胶质母细胞瘤受试者中的应用。 我们的药理学和基因组学成像核心将促进临床材料的研究 （PGIC）。PGIC将允许我们使用MALDI质量来量化CM 93的肿瘤内积累。 使用单细胞光谱成像来确定CM 93治疗对肿瘤异质性的影响， 测序总的来说，这些研究有望为EGFR驱动的GBM产生新的靶向治疗方法， 提供了对这些药物敏感性和耐药性决定因素的分子理解。