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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要表皮雌性因子受体（EGFR）基因在超过一半的GBM中被静音或扩增突变和局灶性扩增与更具侵略性的疾病病程相关。酪氨酸激酶抑制剂（TKI）未能显示出这种疾病的功效，这些失败不能是严格归因于大脑的渗透率。一个治疗窗口。（NSCLC）是绝对必需的突变选择性。（WT）EGFR信号是NSCLC中的剂量限制性毒品。相对于WT EGFR，对某些EGFR TKI的敏感性增强了，允许真正的突变体选择性抑制作用。信号生成域的信号几乎完全是结构中的WT。 EGFR TKI带有ABELRANT EGFR信号的治疗窗口，我们有两个特定的目标。 AIM 1是检验以下假设：具有作用的同种动物的EGFR TKI 块中与配体无关EGFR信号在GBM中，同时保留配体激活的EGFR系统，此处提供一个治疗窗口，可以在初步研究中对EGFR驱动的GBM进行治疗。我们已经开发了小分子变构抑制剂，可有效抑制WT EGFR（IC50 <100 nm 生化测定），具有良好的口服小鼠PK曲线，并且是脑培训剂在患者衍生的GBM神经圈和异种移植模型中，我们希望确定合适的补充对于在第一个赠款年份进行临床开发，以实现临床翻译。 AIM 2，利用CM93，这是一个新型的第三代EGFR TKI，我很高pentrant-so-so 实际上，它显示了阳性的大脑/血浆比率。事实上的“基于组织”的治疗窗口允许EGFR在肿瘤中具有相对保留从系统的角度来剂量扩张研究，以及一项手术“机会统一窗口”研究，以确定最大耐受性剂量，评估Oraly的安全性，药代动力学，药效学和临床作用 CM93在具有EGFR突变或扩增为特征的复发性胶质母细胞瘤受试者中。我们的药理和基因组成像核心将促进有关临床材料的研究（PGIC）。光谱成像并定义了使用单细胞的CM93处理对肿瘤异质性的影响这些研究共同确定了针对EGFR驱动的GBM的新的靶向治疗方法提供对敏感性和抗性抗性的决定因素的分子理解。