Project Details
Description
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.
Status | Finished |
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Effective start/end date | 4/1/21 → 3/31/24 |
Funding
- National Cancer Institute: $333,654.00
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