Date of Award

Summer 5-28-2025

Embargo Period

5-28-2027

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

College

College of Graduate Studies

First Advisor

Saverio Gentile

Second Advisor

John O’Bryan

Third Advisor

Ozgur Sahin

Fourth Advisor

Aaron Hobbs

Fifth Advisor

Michael Ostrowski

Abstract

Bioelectricity, the regulation of membrane potential through ion channels and transporters, is essential for cellular processes such as proliferation, signaling, and survival. Despite its central role, bioelectric signaling remains an underexplored area in cancer research.

Our work has shown that high expression of specific ion channels—including the surface potassium channel Kv11.1, mitochondrial KCa3.1, and calcium channel TRPA1—is associated with improved prognosis in cancers of various histologies. We hypothesized that pharmacological activation of these channels would produce anticancer effects. Using selective activators, including FDA-approved drugs, we demonstrated that activation of each channel disrupts multiple cancer hallmarks, such as uncontrolled proliferation and metabolic reprogramming, without inducing significant toxicity.

Mechanistically, activation of KCa3.1 in breast cancer and Kv11.1 in lung cancer promotes tumor arrest by inducing a senescent-like phenotype and promoting degradation of key oncogenes like c-Myc and estrogen receptor alpha. In colon cancer, TRPA1 activation leads to cell death via oxidative stress and inhibition of EGFR signaling. Furthermore, ion channel activation enhances responsiveness to existing therapies and helps overcome drug resistance.

Notably, Kv11.1 activation also triggers a lethal immune response against senescent cancer cells. This response is driven by the senescence-associated secretory phenotype (SASP), which includes cytokines and chemokines that recruit immune effector cells. This leads to immune-mediated tumor clearance via TNFα signaling.

To improve delivery and reduce systemic toxicity, we developed a Smart Injectable Hydrogel (SIHD) loaded with NS1643 (SIHD-Ka), a Kv11.1 activator. SIHD enables sustained, localized drug release over three weeks under physiological conditions. In preclinical triple-negative breast cancer (TNBC) models, SIHD-Ka significantly inhibited tumor growth without notable adverse effects.

Given its efficacy, safety, and mechanistic clarity, our strategy is ready for clinical translation. We are preparing a Phase II clinical trial to test KCa3.1 activation using the FDA-approved molecule chlorzoxazone in ER-positive breast cancer patients unresponsive to standard therapies. This work pioneers a new class of bioelectrically targeted cancer treatments with strong translational potential.

Rights

Copyright is held by the author. All rights reserved.

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