Molecular mechanism of EGFRs protein-protein interaction inhibition by a grafted peptide in NSCLC

NSCLC中移植肽抑制EGFR蛋白-蛋白相互作用的分子机制

基本信息

批准号：
10095909
负责人：
DANIEL D BILLADEAU
金额：
$ 32.97万
依托单位：
UNIVERSITY OF LOUISIANA AT MONROE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10095909
关键词：
Animal Cancer Model Antibodies Automobile Driving Binding Biological Availability Biological Products Cancer Patient Cancer cell line Cell model Chemicals Clinical Development Dimerization Drug Kinetics Drug Targeting ERBB3 gene Epidermal Growth Factor Receptor Exhibits Extracellular Domain Family Gene Amplification Generations Genetic Goals Growth Heterodimerization Homo Human In Vitro Intestines Knowledge Lead Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Oral Outcomes Research Pathologist Pathway interactions Patients Peptides Periodicity Pertuzumab Pharmacologic Substance Phosphotransferases Plants Play Process Property Protein Overexpression Proteins Reporting Research Research Project Grants Resistance Resistance development Role Scientist Signal Pathway Signal Transduction Specificity Structure Sunflowers Survival Rate Testing Therapeutic Therapeutic Agents Therapeutic Effect Trypsin Inhibitors Tyrosine Kinase Inhibitor Variant Xenograft Model base cancer cell cancer therapy cancer type design dimer disulfide bond functional group humanized antibody humanized monoclonal antibodies improved in vitro Model in vivo inhibitor/antagonist lung cancer cell malignant breast neoplasm mutant novel novel therapeutic intervention overexpression patient derived xenograft model patient subsets peptide drug peptidomimetics prevent protein protein interaction receptor small molecule targeted treatment therapeutic target therapy resistant tumor tumor growth tumor progression

项目摘要

Project Summary: The long-term objective of this research project is to understand the role of dimerization in extracellular domains (ECD) of epidermal growth factor receptors (EGFRs) in cancer. The short-term goal is to design sunflower trypsin inhibitor (SFTI)-grafted peptides for treatment of lung cancer. Nearly 85% of lung cancer patients have a type of cancer called non-small-cell lung cancer (NSCLC). The five-year survival rate of NSCLC patients has not improved in more than a decade because most tyrosine kinase inhibitors (TKIs) develop resistance to therapy within five years. Dimerization of EGFRs (EGFR, HER2, HER3) is known to play a key role in NSCLC. Apart from EGFR, human epidermal growth factor receptor-2 (HER2) gene amplification and HER2 protein overexpression or mutation seem to play major roles in the development of resistance in NSCLC therapy. Although HER2 overexpression or mutation is observed in 2-4% of NSCLC, HER2 may be a driver of both NSCLC progression and resistance to EGFR. Understanding the details of dimers of EGFRs and inhibiting dimerization has a significant impact on not only HER2 overexpressed but EGFR-mutated NSCLC, and this would fill a gap in our knowledge. Inhibition of EGFRs extracellular domain dimerization has a significant impact on its therapeutic effect on NSCLC. This will be done by targeting the clinically validated target domain IV of human epidermal growth factor receptor-2 (HER2) with peptides. However, peptides have limitations in terms of oral bioavailability. Multicyclic peptides with a disulfide bond such as sunflower trypsin inhibitors are known to have a stable structure that is resistant to thermal, chemical, and enzymatic degradation. These peptides can be grafted with functional groups that can inhibit protein-protein interactions. Grafted peptides overcome the limitations of peptides as therapeutic agents and are orally available. A grafted peptidomimetic molecule has been designed that specifically binds to the HER2 protein and inhibits the dimerization process of EGFR proteins. This approach is novel because the molecule designed disrupts EGFR homo- as well as heterodimers. The molecular mechanism of how the grafted peptide inhibits EGFR dimerization and alters the signaling for cancer is not well understood. We propose to characterize details of the mechanism of inhibition of EGFR dimerization and the biopharmaceutical properties of the grafted peptide. As a proof-of-concept, the grafted peptide will be evaluated in different models of lung cancer, including patient-derived cancer cell model in mice. Aims in this project are: 1) to evaluate the molecular mechanism of protein-protein interactions of EGFRs via inhibition by the grafted peptide and its effect on downstream signaling in HER2-activated and EGFR-resistant lung cancer cells; 2) to evaluate the therapeutic effect of grafted peptides on reducing the growth of lung tumors in mice; 3) to evaluate the oral availability and biopharmaceutical properties of grafted peptides. Such grafted peptides that are orally available will have an impact on lung cancer treatments that develop resistance and on the survival rate of lung cancer patients.

项目摘要：该研究项目的长期目标是了解二聚体的作用表皮生长因子受体（EGFR）的细胞外域（ECD）。短期目标是设计向日葵胰蛋白酶抑制剂（SFTI）嫁接的肽用于治疗肺癌。近85％的肺癌患者患有一种称为非小细胞肺癌（NSCLC）的癌症。 NSCLC的五年生存率十多年来，患者没有改善，因为大多数酪氨酸激酶抑制剂（TKIS）发展在五年内抵抗治疗。众所周知，EGFR（EGFR，HER2，HER3）的二聚化起着关键作用在NSCLC中。除EGFR外，人表皮生长因子受体2（HER2）基因扩增和HER2 蛋白质过表达或突变似乎在NSCLC治疗的耐药性发展中起着重要作用。尽管在2-4％的NSCLC中观察到HER2过表达或突变，但HER2可能是两者的驱动力 NSCLC的进展和对EGFR的抗性。了解EGFR二聚体的细节并抑制二聚化不仅对HER2过表达，而且对EGFR突变的NSCLC产生了重大影响，这将填补我们的知识。抑制EGFRS细胞外域二聚化具有显着影响关于其对NSCLC的治疗作用。这将通过针对临床验证的目标域IV来完成用肽的人表皮生长因子受体-2（HER2）。但是，肽在口服生物利用度。已知具有二硫键的多环肽，例如向日葵胰蛋白酶抑制剂具有抗热，化学和酶促降解的稳定结构。这些肽可以用可以抑制蛋白质蛋白相互作用的功能组接枝。接枝肽克服了肽作为治疗剂的局限性，并且可以口服。接枝肽分子的分子被设计为特异性结合HER2蛋白并抑制EGFR蛋白的二聚化过程。这种方法是新颖的，因为该分子设计的破坏了EGFR均匀和异二聚体。这移植肽如何抑制EGFR二聚化并改变癌症信号的分子机制不太了解。我们建议表征抑制EGFR Dimerization机制的细节以及移植肽的生物药物特性。作为概念验证，接枝的肽将是在不同模型的肺癌模型中进行了评估，包括小鼠的患者来源的癌细胞模型。目的是项目是：1）评估EGFR蛋白质蛋白质相互作用的分子机制通过抑制嫁接的肽及其对HER2激活和EGFR耐药性肺癌中下游信号传导的影响细胞； 2）评估移植肽对减少小鼠肺部肿瘤生长的治疗作用； 3）评估移植肽的口服可用性和生物药物特性。这种接枝的肽口服可用会对发展抗性和生存的肺癌治疗产生影响肺癌患者的发生率。