Author ORCID Identifier

https://orcid.org/0000-0003-1998-6204

Semester

Summer

Date of Graduation

2026

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Paul R. Lockman

Committee Member

Werner Geldenhuys

Committee Member

Sharan Bobbala

Committee Member

David A. Clump

Committee Member

Jeffrey Carpenter

Abstract

This dissertation (a) provided a comprehensive review of the known therapeutic challenges in nicotine delivery system users with lung cancer and (b) investigated the impact of electronic cigarettes on blood-brain/blood-tumor barrier function and efficacy of small molecule KRAS inhibitors in a syngeneic lung cancer brain metastasis model. The blood-brain barrier is a physiochemical barrier that limits systemic delivery of therapeutics into brain. When tumors invade the central nervous system, the blood-brain barrier is disrupted and subsequently forms a blood-tumor barrier. Despite the inherent leakiness and variable permeability of the blood-tumor barrier, it continues to restrict anti-cancer drugs from accumulating at therapeutic concentrations. Electronic cigarettes are shown to negatively impact blood-brain barrier function. Whether this results in changes in drug delivery and/or progression of brain metastases remains unknown. This is of importance due to the effects of smoking on lung cancer progression and increasing popularity of electronic cigarette use in smoking-related cancers. Our findings show that although electronic cigarettes do not disrupt the integrity of the blood-brain barrier, exposure increases the activity of efflux transporters. This results in reduced efficacy of adagrasib, a recently approved KRAS inhibitor that is subject to efflux at the blood-brain barrier. This work emphasizes the physiological impacts of electronic cigarettes on progression of brain metastases by reducing delivery of anti-cancer therapeutics.

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