Degree

Doctor of Biomedical and Veterinary Medical Sciences-Pathobiological Sciences (PVMPB)

Department

Department of Pathobiological Sciences

Document Type

Dissertation

Abstract

Lung cancer accounts for approximately 20% of the cancer-related deaths in the United States, with a five-year survival rate of roughly 29%. The current treatment modalities for Non-small cell lung cancer (85% of lung cancer cases) are limited to chemotherapies, small molecules like tyrosine kinase inhibitors, and immunotherapies, which often face limitations due to non-specificity, development of resistance, and poor oral bioavailability, respectively. In this work, we investigated a novel cyclic peptidomimetic, SFTI-G5, designed to inhibit HER2 dimerization and as a potential therapeutic strategy for NSCLC and to overcome the limitations of conventional therapeutics.

Initially, SFTI-G5 was tested in a HER2-expressing Calu-3 Xenograft model, in which SFTI-G5, upon oral administration at a dose of 50 mg/kg, significantly reduced tumor volume (up to 74%) with an excellent safety profile and acceptable oral bioavailability. To characterize the HER2 specificity of SFTI-G5, we tested SFTI-G5 at an intravenous dose of 6 mg/kg in patient-derived xenograft (PDX) models with low and high HER2 expression. SFTI-G5 showed an HER2-dependent profile, with a significant reduction in tumor volume observed in the HER2-overexpressing model (around 40%), whereas no change in tumor volume was observed in the HER2-downregulated PDX model.

Furthermore, we demonstrated that the activity of SFTI-G5 could be expanded into EGFR mutant models such as EGFRL858R models, in which a significant reduction in tumor volume was observed (around 30%) due to inhibition of dimerization of activated EGFR with HER2 receptor. In PDX and xenograft models, there was no significant change in body weight, no morphological changes in organ sections, and no significant change in blood serum chemistry, which highlights the excellent safety profile of SFTI-G5. Furthermore, a computational study of SFTI-G5 binding to HER2 domain IV revealed that SFTI-G5 binds to the trastuzumab binding site. Direct binding and heterodimerization were validated in engineered HEK293T cells expressing EGFR: HER2 and HER2:HER3.Finally, SFTI-G5 was developed into a peptide film formulation, which helped to mitigate pH-dependent solubility.

Overall, this dissertation established SFTI-G5 as an orally active HER2-specific peptidomimetic with an extracellular domain-targeting mechanism. These findings support the further development of SFTI-G5 for HER2-driven NSCLC, opening new therapeutic modalities for NSCLC.

Date

10-20-2026

Committee Chair

Jois, Seetharama

LSU Acknowledgement

1

LSU Accessibility Acknowledgment

1

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Available for download on Monday, October 15, 2029

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