Targeting glioblastoma with CM93, a novel EGFR inhibitor with exceptional brain penetration

使用 CM93 靶向胶质母细胞瘤，这是一种具有出色脑渗透性的新型 EGFR 抑制剂

基本信息

批准号：
10697498
负责人：
Jean Zhao
金额：
$ 40万
依托单位：
CRIMSON BIOPHARM INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10697498
关键词：
Address Adult Advanced Development Affinity Aftercare Animals Apoptosis Binding Biological Markers Blood Brain Brain Neoplasms CDK4 gene CDKN2A gene Cells Central Nervous System Central Nervous System Agents Central Nervous System Neoplasms Clinical Clinical Research Clinical Trials DNA Dana-Farber Cancer Institute Development Disease Dose Drug Targeting EGFR gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Failure Generations Genetic Glioblastoma Implant Joints Knock-out Legal patent Licensing Malignant Neoplasms Modeling Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Patients Penetration Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phosphotransferases Preparation Property Receptor Inhibition Receptor Signaling Resistance Safety Signal Pathway Small Business Innovation Research Grant Small Business Technology Transfer Research Testing Therapeutic Therapeutic Agents Toxic effect Treatment Efficacy Tyrosine Kinase Domain United States National Institutes of Health Variant Work biomarker development blood-brain barrier crossing cancer cell cancer therapy cancer type clinical investigation commercialization design first-in-human inhibitor mutant neuro-oncology neurotoxicity novel novel therapeutics patient derived xenograft model potential biomarker pre-clinical response senescence small molecule success systemic toxicity targeted treatment therapeutic target transcriptome sequencing translational study tumor virtual

项目摘要

PROJECT SUMMARY The epidermal growth factor receptor (EGFR) gene is mutated and/or amplified in majority of primary glioblastoma (GBM). While EGFR-mutant GBM cancer cells are dependent on EGFR signaling for survival, numerous small molecule EGFR tyrosine kinase inhibitors (TKIs) have failed to show efficacy in this disease. There are two main reasons for these failures: i) Many of these EGFR-TKIs fail to cross the blood-brain barrier (BBB); ii) These EGFR-TKIs were developed to specifically target mutant EGFRs with mutations in the kinase domain found in non-small cell lung cancer (NSCLC), but they have poor activity (low binding affinity) against GBM EGFR variants with a wild-type tyrosine kinase domain. CM93 has been developed at Crimson Biopharm as a novel therapeutic agent to specifically tackle these challenges in treating GBM. CM93 has distinct features that set it apart from all other EGFR-TKIs, including osimertinib. CM93 is highly enriched in the brain, with an exceedingly low blood concentration (>2,000% brain penetration). This extraordinary property of CM93, in conjunction with its high potency against EGFR with wild-type tyrosine kinase domain, offers a powerful and unique opportunity for CM93 to effectively inhibit GBM with EGFR variants without significant systemic toxicity. Notably, CM93 has received IND approval for the first-in-human phase 1 clinical trial in GBM patients and is currently part of NIH/NCI’s “Glioblastoma Therapeutics Network (GTN)” to conduct phase 1 and surgical window studies led by Dr. Patrick Wen, Director of Neuro-Oncology at Dana-Farber Cancer Institute (DFCI). The overall objective of this STTR application is to evaluate the combination of CM93 with abemaciclib (an approved CDK4/6 inhibitor with notable CNS activity as proposed in Aim1 and biomarker analyses in Aim 2 in patient-derived GBM models to provide important pre-clinical proof of concept to better support CM93’s first-in-human phase 1 and window-of-opportunity surgical studies.

项目概要大多数表皮生长因子受体 (EGFR) 基因发生突变和/或扩增原发性胶质母细胞瘤 (GBM) EGFR 突变的 GBM 癌细胞依赖于 EGFR。许多小分子 EGFR 酪氨酸激酶抑制剂 (TKI) 都失败了这些失败的主要原因有两个： i) 其中许多原因。 EGFR-TKI 无法穿过血脑屏障 (BBB)； ii) 这些 EGFR-TKI 的开发目的是特异性靶向非小细胞肺中发现的激酶结构域突变的突变 EGFR 癌症 (NSCLC)，但它们针对 GBM EGFR 变异体的活性较差（结合亲和力低） CM93 具有野生型酪氨酸激酶结构域，已由 Crimson Biopharm 开发。专门应对治疗 GBM 的这些挑战的新型治疗剂具有独特的特点。它与所有其他 EGFR-TKI（包括奥希替尼）的高度富集特征不同。在大脑中，血液浓度极低（> 2,000% 大脑渗透）。 CM93 的非凡特性及其针对野生型 EGFR 的高效力酪氨酸激酶结构域，为 CM93 提供强大且独特的机会来有效抑制具有 EGFR 变异的 GBM，没有显着的全身毒性值得注意的是，CM93 已获得 IND。批准在 GBM 患者中进行首次人体 1 期临床试验，目前是 NIH/NCI 的“胶质母细胞瘤治疗网络 (GTN)”将进行第一阶段和手术窗口由丹娜—法伯癌症研究所神经肿瘤学主任 Patrick Wen 博士领导的研究 (DFCI) 此 STTR 应用的总体目标是评估 CM93 与的组合。 abemaciclib（一种已批准的 CDK4/6 抑制剂，具有 Aim1 中提出的显着 CNS 活性和 Aim 2 中患者来源的 GBM 模型中的生物标志物分析可提供重要的临床前证据更好地支持 CM93 的首次人体 1 期和机会窗口手术的概念研究。