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

Award Number: R01CA255176
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $339,816 )
2025	2025	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Cancer Treatment Research	004	6	5/22/2025	NON-COMPETING CONTINUATION	$33,982
2025	2025	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Cancer Treatment Research	003	6	3/11/2025	NON-COMPETING CONTINUATION	$305,834
2025	2023	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVENUE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	001	3	1/21/2025	NON-COMPETING CONTINUATION	-$16,384
2025	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Cancer Treatment Research	002	4	1/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$40,369
2025	2022	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVENUE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	000	2	1/21/2025	NON-COMPETING CONTINUATION	-$23,985
														Subtotal = $339,816

Issue Date FY: 2024 ( Subtotal = $328,309 )
2024	2024	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Cancer Treatment Research	000	5	3/8/2024	NON-COMPETING CONTINUATION	$311,029
2024	2024	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Cancer Treatment Research	001	5	4/18/2024	NON-COMPETING CONTINUATION	$17,280
														Subtotal = $328,309

Issue Date FY: 2023 ( Subtotal = $350,038 )
2023	2023	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVENUE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	000	3	3/25/2023	NON-COMPETING CONTINUATION	$323,057
2023	2023	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVENUE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	001	3	6/30/2023	NON-COMPETING CONTINUATION	-$306,673
2023	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Cancer Treatment Research	002	4	6/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$333,654
														Subtotal = $350,038

Issue Date FY: 2022 ( Subtotal = $323,057 )
2022	2022	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	002	2	5/23/2022	NON-COMPETING CONTINUATION	$26,372
2022	2022	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	001	2	3/17/2022	NON-COMPETING CONTINUATION	$296,685
2022	2021	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	000	1	2/15/2022	NEW	$0
														Subtotal = $323,057

Issue Date FY: 2021 ( Subtotal = $329,651 )
2021	2021	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Cancer Treatment Research	000	1	3/26/2021	NEW	$329,651
														Subtotal = $329,651

Grand Total All Awards = $1,670,871

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

Award Number: R01CA255176

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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