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.

项目摘要 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 尽管EGFR酪氨酸激酶抑制剂（TKI）是一种用于生存的信号传导，但许多小分子EGFR酪氨酸激酶抑制剂（TKI）已经失败， 来证明对这种疾病的疗效。这些失败的主要原因有两个：i）其中许多 EGFR-TKI不能穿过血脑屏障（BBB）; ii）开发这些EGFR-TKI， 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），但它们对GBM EGFR变体的活性差（低结合亲和力 具有野生型酪氨酸激酶结构域。CM 93由Crimson Biopharm开发， 新型治疗药物专门解决治疗GBM的这些挑战。CM 93具有独特的 这些特征使其有别于所有其他EGFR-TKI，包括奥希替尼。CM 93高度浓缩 在大脑中，具有极低的血液浓度（> 2，000%的大脑渗透）。这 CM 93的特殊性质，连同其对野生型EGFR的高效力， 酪氨酸激酶结构域，为CM 93提供了强大而独特的机会，以有效抑制 具有EGFR变体的GBM，无显著全身毒性。值得注意的是，CM 93已收到IND 批准在GBM患者中进行首次人体I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1阶段和手术窗口期 丹娜-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）。该STTR应用的总体目标是评估CM 93与 abemaciclib（一种获批的CDK 4/6抑制剂，具有显著的CNS活性，如Aim 1中所述， 在患者源性GBM模型中进行目标2中的生物标志物分析，以提供重要的临床前证据 概念，以更好地支持CM 93的第一次在人体中的第一阶段和机会窗口手术 问题研究