Development of a first-in-class mEGFR dimerization inhibitor

开发一流的 mEGFR 二聚化抑制剂

基本信息

批准号：
10591476
负责人：
THEODORE S LAWRENCE
金额：
$ 41.08万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591476
关键词：
Address Advanced Development Area Binding Biodistribution Biological Availability Cancer Patient Cancer cell line Cell Death Cell Line Cell Survival Cells Chronic Clinical Clinical Research Clinical effectiveness Data Development Diagnosis Dimerization Dose Drug Exposure Drug Kinetics Effectiveness Epidermal Growth Factor Receptor Exposure to Frequencies Future Generations Genes Goals Immunocompetent In Vitro Knowledge Luciferases Lung Neoplasms Malignant neoplasm of lung Methods Modeling Monitor Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Normal Cell Null Lymphocytes Oncogenic Oral Oral Administration Organ Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Plasma Positron-Emission Tomography Probability Progression-Free Survivals Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Regimen Research Design Resistance Resistance development Safety Schedule Series Specificity Statistical Models Study models Therapeutic Tissues Toxic effect Treatment Efficacy Treatment Protocols Tyrosine Kinase Inhibitor Xenograft Model Xenograft procedure cancer cell cancer imaging cancer therapy chemotherapy clinically relevant design efficacy evaluation improved outcome in vivo in vivo evaluation inhibitor inhibitor therapy lung cancer cell lung xenograft mouse model mutant neoplastic cell novel patient derived xenograft model pharmacokinetics and pharmacodynamics pre-clinical protein expression receptor receptor expression refractory cancer resistance mutation response small molecule targeted agent therapy resistant treatment effect treatment response tumor tumor progression

项目摘要

Background: Lung cancers are often driven by mutant epidermal growth factor receptor (mtEGFR). While EGFR tyrosine kinase activity inhibitors (TKI) have shown effectiveness, within 9-13 months all patients develop resistance including to 3rd generation TKI - Osimertinib. These patients do not have any approved therapy options, therefore, there is an urgent need to develop a novel agent that functions independently of kinase function. DGD1202, a first-in-class, novel, orally bioavailable, small molecule that inhibits EGFR dimerization, induces degradation of EGFR and selectively kills TKI resistant NSCLC tumors. Objective: We and others have shown that the degradation of mutant EGFR protein has a profound effect on cancer cell survival. Thus, we hypothesized that a drug which induces degradation of mtEGFR independent of the ATP binding domain will result in selective activity. Our objective is to evaluate the therapeutic potential of DGD1202 in a panel of lung cancer cells lines, xenografts, and PDXs derived from lung cancer patients containing mtEGFR who have undergone treatment with a TKI. Specific Aims: We propose to evaluate the specificity and potency of DGD1202 against TKI-resistant lung cancer cells and xenografts. Aim 1 is to determine the in vitro efficacy of DGD1202 against a panel of EGFR driven, including osimertinib-resistant, cancer cell lines relative to normal cells. Aim 2 is to conduct in vivo pharmacokinetic (PK) and pharmacodynamic (PD) analyses to assess drug exposure and determine the effect on the target. Aim 3 is to determine the overall therapeutic efficacy and long-term safety of DGD1202 in vivo. We hypothesize that treatment with DGD1202 will induce EGFR degradation preferentially in tumor cells driven by mtEGFR and that EGFR degradation will correlate with the overall response. Study Design: We will screen DGD1202 alongside osimertinib in a series of lung cancer lines. The resulting response will be then correlated with effect on EGFR degradation. We also propose to determine in vivo PK and PD studies both with a single and with fractionated dosing to determine the optimum bioavailability. Using the optimized dose and schedule, we will assess effects on EGFR protein against a panel mtEGFR-driven and osimertinib resistant lung cancer xenograft and PDX models. The long-term safety will be assessed in immune competent mice. Standard statistical models will be used to compare the response to treatment and how it correlates with effects on EGFR. Impact: We anticipate that our approach will open a new way to target EGFR and, more broadly, to develop therapeutics to selectively target mutated proteins to degradation. The knowledge gained from in vivo tumor models will provide a rationale for the use of this class of molecules in future clinical studies.

背景：肺癌通常是由突变的表皮生长因子受体（mtEGFR）驱动的。尽管 EGFR 酪氨酸激酶活性抑制剂 (TKI) 在 9-13 个月内对所有患者显示出有效性产生耐药性，包括对第三代 TKI - 奥希替尼 (Osimertinib) 的耐药性。这些患者没有获得任何批准因此，迫切需要开发一种独立于治疗选择的新型药物激酶功能。 DGD1202，一种一流的、新型的、口服生物可利用的、抑制 EGFR 的小分子二聚化，诱导 EGFR 降解并选择性杀死 TKI 耐药 NSCLC 肿瘤。目的：我们和其他人已经证明突变型 EGFR 蛋白的降解对癌细胞存活。因此，我们假设有一种药物能够独立地诱导 mtEGFR 降解。 ATP 结合域将导致选择性活性。我们的目标是评估治疗潜力一组肺癌细胞系、异种移植物和源自肺癌患者的 PDX 中的 DGD1202 含有 mtEGFR 并接受过 TKI 治疗的人。具体目标：我们建议评估 DGD1202 针对 TKI 耐药肺的特异性和效力癌细胞和异种移植物。目标 1 是确定 DGD1202 针对一组 EGFR 的体外功效相对于正常细胞，包括对奥希替尼耐药的癌细胞系。目标2是在体内进行药代动力学 (PK) 和药效学 (PD) 分析，以评估药物暴露并确定效果在目标上。目标 3 是确定 DGD1202 体内的总体治疗效果和长期安全性。我们假设 DGD1202 治疗将优先诱导肿瘤细胞驱动的 EGFR 降解 mtEGFR 和 EGFR 降解将与总体反应相关。研究设计：我们将在一系列肺癌细胞系中筛选 DGD1202 和奥西替尼。由此产生的然后将反应与对 EGFR 降解的影响相关联。我们还建议确定体内 PK 以及单次给药和分次给药的 PD 研究，以确定最佳生物利用度。使用优化的剂量和时间表，我们将针对一组 mtEGFR 驱动和评估对 EGFR 蛋白的影响奥希替尼耐药肺癌异种移植和 PDX 模型。长期安全性将在免疫方面进行评估有能力的老鼠。标准统计模型将用于比较治疗的反应以及治疗效果如何与 EGFR 的影响相关。影响：我们预计我们的方法将为靶向 EGFR 开辟一条新途径，更广泛地说，将开发选择性靶向突变蛋白质进行降解的治疗方法。从体内肿瘤获得的知识模型将为在未来的临床研究中使用此类分子提供理论依据。