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：肺癌通常由突变表皮生长因子受体（MTEGFR）驱动。尽管 EGFR酪氨酸激酶活性抑制剂（TKI）在9-13个月内显示出有效性发展抗性，包括第三代TKI -Osimertinib。这些患者没有任何批准因此，治疗选择迫切需要开发一种独立于功能的新型药物激酶功能。 DGD1202，一种抑制EGFR的一类新型，新颖的口服生物可利用的小分子二聚化，诱导EGFR的降解并有选择地杀死TKI抗TKI NSCLC肿瘤。目的：我们和其他人表明，突变体EGFR蛋白的降解对癌细胞存活。因此，我们假设一种诱导MTEGFR降解的药物独立于 ATP结合域将导致选择性活动。我们的目标是评估 DGD1202在肺癌细胞系，异种移植物和PDX中的DGD1202衍生自肺癌患者包含接受TKI治疗的MTEGFR。具体目的：我们建议评估DGD1202对TKI肺的特异性和效力癌细胞和异种移植物。 AIM 1是确定DGD1202对EGFR面板的体外功效驱动的，包括抗osimertinib的癌细胞系相对于正常细胞。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影响在目标上。目标3是确定DGD1202在体内的总体治疗功效和长期安全性。我们假设DGD1202的治疗将优先诱导EGFR降解 MTEGFR和EGFR降解将与整体响应相关。研究设计：我们将在一系列肺癌系中与Osimertinib一起筛选DGD1202。结果然后，响应将与对EGFR降解的影响相关。我们还建议确定体内PK PD和单一的分数剂量研究以确定最佳的生物利用度。使用优化的剂量和时间表，我们将评估对MTEGFR驱动的面板蛋白的影响 osimertinib抗性肺癌异种移植和PDX模型。长期安全将以免疫进行评估能干的老鼠。标准统计模型将用于比较对治疗的反应及其如何与对EGFR的影响相关。影响：我们预计我们的方法将打开一种针对EGFR的新方法，更广泛地开发治疗剂选择性地靶向突变的蛋白质降解。从体内肿瘤中获得的知识模型将为在未来的临床研究中使用这类分子提供理由。