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.

项目摘要表皮生长因子受体（EGFR）基因在大多数中被突变和/或扩展原发性胶质母细胞瘤（GBM）。而EGFR突变GBM癌细胞依赖于EGFR 生存信号传导，许多小分子EGFR EGFR酪氨酸激酶抑制剂（TKI）失败了在这种疾病中表现出效率。这些失败的主要原因有两个：i）其中许多 EGFR-TKIS未能越过血脑屏障（BBB）； ii）这些EGFR-TKI被开发为特异性靶向突变EGFR，其在非小细胞肺中发现的激酶结构域中突变癌症（NSCLC），但它们的活性较差（结合亲和力低）针对GBM EGFR变体带有野生型酪氨酸激酶结构域。 CM93已在Crimson Biopharm中开发为新型的热剂可以专门应对治疗GBM的挑战。 CM93有独特的将其与包括Osimertinib在内的所有其他EGFR-TKI区分开的功能。 CM93高度丰富在大脑中，血液浓度极低（脑穿透> 2,000％）。这 CM93的非凡特性，以及其对EGFR的高效力与野生型酪氨酸激酶域为CM93提供了有效抑制的强大而独特的机会具有EGFR变体的GBM，没有明显的全身毒性。值得注意的是，CM93已收到IND 在GBM患者中批准了人类第一期临床试验的批准，目前是 NIH/NCI的“胶质母细胞瘤疗法网络（GTN）”进行1阶段和手术窗口 Dana-Farber癌症研究所神经肿瘤学主任Patrick Wen博士领导的研究（DFCI）。该STTR应用的总体目的是评估CM93与 Abemacilib（AIM1和在患者衍生的GBM模型中AIM 2中的生物标志物分析，以提供重要的临床前证明更好地支持CM93的第一阶段1和开放式手术窗口的概念研究。