Graduation Date

Fall 12-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Rebecca Oberley-Deegan

Abstract

Pelvic cancers, including rectal, anal, and prostate cancer, are relatively survivable cancers with high five-year survival rates, partially due to the addition of radiation to treatment regimens. Radiation confers excellent tumor control, but also causes damage to surrounding tissue, resulting in both short-term and long-term side effects. In a patient population that is surviving longer after treatment, limiting the impact of side effects is instrumental to improving patient quality of life. Radiation-induced ROS is instrumental in causing these side effects and provides a unique opportunity to protect healthy tissue from damage while sensitizing cancer tissue to treatment, as cancer cells thrive under levels of ROS that damage healthy cells.

BMX-001, a superoxide dismutase mimetic with potent superoxide scavenging capabilities, is currently in clinical trials as a selective radioprotector when administered before and during radiation therapy for brain, head and neck, endometrial, rectal, and anal cancers. Existing work has established BMX-001’s efficacy as a radioprotector, but few studies have sought to elucidate its mechanism, particularly in the context of physiologically relevant doses, alternative dosing schedules, and in the context of chemotherapy alone. We hypothesize that BMX-001 acts as a chemoradioprotector not only through its activity as a superoxide dismutase mimetic but through a myriad of consequent functions, including via Nrf2 activation, alterations to protein oxidation status, and changes in methylation patterns. We confirmed that BMX-001 does not protect colorectal cancer cells in a hind flank model, and showed that BMX-001 provided robust protection against acute radiation damage in rectal tissue. We demonstrated that BMX-001 enacts chemoradioprotection of bone marrow even in mice that lack functional Nrf2. We found significant alterations in protein sulfenylation in response to BMX-001 in genes responsible for decreasing chemotherapy-induced stress in bone marrow, including CREB regulated transcription coactivator 2 (CRTC2), aldehyde dehydrogenase 7 family member A1 (ALDH7A1), and dihydropyrimidine dehydrogenase (DPYD).

For the first time, we established a novel role for BMX-001 as an agent which can reverse fibrosis, which has therapeutic relevance outside the context of radiation-induced fibrosis. We confirmed that BMX-001 can reverse prototypical markers of fibroblast activation and senescence when administered three weeks after radiation, and that it can prevent fibrosis from occurring via collagen deposition six months after radiation. We validated that BMX-001 can repair radiation-induced changes in methylation and that BMX-001 may reverse fibrosis through expression of a fibrosis-implicated gene, CaMKIIβ. These studies provide both novel functions of BMX-001 as a chemoprotector and as an agent to reverse fibrosis. These studies also provide a novel mechanism for BMX-001 outside its superoxide dismutase activity. Together, this study provides increased rationale for BMX-001’s clinical use and expands potential indications for the use of BMX-001 to maximally benefit patients.

Comments

2025 Copyright, the authors

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