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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：
10850407
负责人：
DANIEL D BILLADEAU
金额：
$ 33.37万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
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/10850407
关键词：
Animal Cancer Model Antibodies Automobile Driving Binding Biological Availability Biological Products Cancer Patient Cancer cell line Cell model Chemicals Clinical Cyclic Peptides 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 Inhibition Protein Overexpression Proteins Reporting Research Research Project Grants Resistance Resistance development Role Scientist Signal Pathway Signal Transduction Specificity Structure Sunflowers Survival Rate Therapeutic Therapeutic Agents Therapeutic Effect Trypsin Inhibitors Tyrosine Kinase Inhibitor Variant Xenograft Model cancer cell cancer therapy cancer type design dimer disulfide bond functional group humanized antibody humanized monoclonal antibodies improved in vitro Model in vivo inhibitor 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 stability testing 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.

项目概述：本研究项目的长期目标是了解二聚化在