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

• 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
• 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

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.

项目总结 表皮生长因子受体(EGFR)基因在大多数人中突变和/或扩增 原发性胶质母细胞瘤(GBM)。而EGFR突变的GBM癌细胞依赖于EGFR 为了生存，许多小分子EGFR酪氨酸激酶抑制剂(TKI)已经失败 以显示对这种疾病的疗效。这些失败主要有两个原因：i)许多 EGFR-TKIs未能通过血脑屏障(BBB)；ii)这些EGFR-TKIs的开发目的是 在非小细胞肺中发现具有激酶结构域突变的特异性靶向突变的EGFR 癌症(NSCLC)，但它们对GBM EGFR变异体的活性较差(结合亲和力低) 带有野生型酪氨酸激酶结构域。CM93已经在深红生物制药公司作为一种 新的治疗剂，专门解决这些挑战，在治疗基底膜。CM93具有明显的 使其有别于所有其他EGFR-TKI的特征，包括osimertinib。CM93高度浓缩 在大脑中，血液浓度极低(&gt；2000%的大脑渗透率)。这 CM93的非凡特性及其对野生型EGFR的高效对抗 酪氨酸激酶结构域，为CM93提供了一个强大而独特的机会来有效抑制 含有EGFR变异体的GBM没有明显的全身毒性。值得注意的是，CM93已获得IND 批准在GBM患者中进行第一个人类阶段1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 达纳-法伯癌症研究所神经肿瘤学主任帕特里克·温博士领导的研究 (DFCI)。此STTR应用程序的总体目标是评估CM93与 Abemaciclib(一种批准的CDK4/6抑制剂，具有显著的中枢神经系统活性，如在Aim1和 AIM 2在患者源性GBM模型中的生物标志物分析为临床前提供重要证据 更好地支持CM93的S人类第一阶段和机会之窗手术的理念 学习。