Event
PhD Dissertation Defense: Idrisa Rahman
Monday, April 7, 2025
1:00 p.m.
AJC 3104 (3rd floor conference room)
Rachel Chang
301 405 8268
rachel53@umd.edu
Title: Targeting Cellular Metabolism by Leveraging Verteporfin to Overcome Cancer Multidrug Resistance
Committee members:
Dr. Huang-Chiao Huang, Chair
Dr. Alisa Clyne
Dr. Michael M. Gottesman
Dr. Andaleeb Sajid
Dr. Amy Karlsson, Dean's Representative
Abstract:
Multidrug resistance (MDR) remains one of the greatest challenges in cancer chemotherapy, often leading to treatment failure. P-glycoprotein (P-gp), a well-characterized ATP-binding cassette (ABC) drug efflux transporter, is a major contributor to MDR by actively removing chemotherapeutic agents from cancer cells. Despite decades of research, no clinically approved P-gp inhibitors exist due to concerns about toxicity and lack of selectivity. This underscores the need for alternative strategies beyond traditional small-molecule inhibitors and antibodies to effectively reverse MDR.
Photodynamic therapy (PDT) has emerged as a promising alternative due to its high selectivity and minimal systemic toxicity. PDT employs red light to activate photosensitizers like verteporfin (VP), generating reactive oxygen species (ROS) to ablate tumors. While PDT primarily aims to kill cancer cells, lower light doses - known as photodynamic priming (PDP) - can achieve sub-therapeutic effects that modulate cellular functions. Our lab has previously demonstrated that VP-PDT can reduce ABC transporter expression by inducing protein crosslinking, thereby impairing efflux function. However, given that ABC transporters are ATP-driven, an unexplored avenue for P-gp inhibition lies in targeting cellular metabolism to deplete ATP and indirectly reduce efflux activity. Additionally, the dark (non-photoactivated) effects of VP on P-gp function remain understudied in the context of chemoresistance.
The overall objective of this dissertation was to investigate the hypothesis that VP can inhibit P-gp function both directly, via photoactivation-induced crosslinking, and indirectly, by depleting ATP with and without light activation. To test this hypothesis, I utilized in vitro models of drug-sensitive and drug-resistant triple-negative breast cancer (TNBC) cells across three specific aims. In Aim 1, I investigated how photodynamic priming modulates cellular energetics and ATP levels to decrease P-gp function. In Aim 2, I explored how molecular and nanoengineering approaches enhance P-gp inhibition using photodynamic priming in drug-resistant cancer cells. Finally, in Aim 3, I evaluated how light-independent VP treatment affects P-gp function, shedding light on its potential as a metabolic inhibitor in overcoming MDR. By uncovering new strategies to inhibit P-gp through both photodynamic and metabolic approaches, this work lays the foundation for more effective, selective, and clinically translatable solutions to overcome multidrug resistance, ultimately improving treatment outcomes for patients with aggressive cancers.
