ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Thesis
Degree Name
Master of Science (MS)
Programs
Immunology, Pathology & Infectious Disease
First Advisor
Kurt W. Fisher
Second Advisor
Nick T. Woods
Third Advisor
Jennifer Black
Abstract
Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths globally, highlighting the need for improved therapeutic strategies. Peroxisome proliferator-activated receptor γ coactivator 1 beta (PGC-1β) is a promising therapeutic target; however, no known direct inhibitors exist. As a transcriptional coactivator, PGC-1β requires interacting proteins to promote transcription of metabolic genes that support CRC growth. To identify these proteins, PGC-1β was immunoprecipitated and analyzed by mass spectrometry to establish protein binding partners. Estrogen-related receptor alpha (ERRα) was identified as the sole transcription factor that interacts with PGC-1β. Given that ERRα is well characterized in other cancers, using a novel ERRα inhibitor was thought to decrease cell proliferation in aggressive CRC. Five ERRα inhibitors were evaluated in patient derived CRC organoids, enabling a physiologically relevant model. Several inverse agonists showed minimal inhibition of ERRα at 10µM concentration. In contrast, PROTACs that specifically bind to ERRα, showed a complete degradation of ERRα at 10µM concentrations. A comparison of VHL and MDM2 recruiting PROTACs revealed that the VHL-recruiting PROTAC had a stronger rate of degradation, with its specificity confirmed by mass spectrometry. A cell viability assay and a dual-targeting approach were performed to demonstrate that combining a chemotherapeutic agent and a PROTAC reduced tumor viability more efficiently. Collectively, these findings support ERRα degradation through a VHL-based PROTAC as a promising novel therapeutic strategy for targeting aggressive CRC.
Rights
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Recommended Citation
Reynolds, Kamryn A., "Targeting ERRα in the PGC-1β Signaling Cascade in Aggressive Colorectal Cancer" (2026). Theses & Dissertations. 1070.
https://digitalcommons.unmc.edu/etd/1070