Combinatorial Treatment with Small Molecule Inhibitors of AEG-1 and MYC for Hepatocellular Carcinoma
Author ORCID Identifier
https://orcid.org/0000-0001-9520-6412
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Microbiology & Immunology
First Advisor
Devanand Sarkar
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Two oncogenes, Astrocyte Elevated Gene-1 (AEG-1) and MYC, are co-amplified in HCC patients and cooperate to promote aggressive, metastatic HCC. MYC is a driver oncogene, its overexpression can initiate HCC, while AEG-1’s overexpression cannot. AEG-1 can significantly accelerate tumor progression once initiated. This study assessed the therapeutic efficacy of combining the small molecule inhibitors C26-A6 (AEG-1 inhibitor) and MYCi975 (MYC inhibitor) against HCC. Human HCC cell lines HuH-7, SNU-449, and SNU-182 were treated with C26-A6 and MYCi975, both alone and in combination. MTT, colony formation, invasion, and wound healing assay data showed that combination of C26-A6 and MYCi975 showed significant and synergistic inhibition in viability, invasion, and migration compared to single treatment. Annexin V/FITC experiments confirmed that the combinatorial treatment induces apoptosis. SNU-449 cells were treated with C26-A6, MYCi975, or C26-A6+MYCi975 combination for 24 hours and RNA-seq was performed. Analysis of differentially expressed genes revealed that MYCi975 inhibited pathways associated with cell proliferation, C26-A6 inhibited pathways regulating metastasis, and the combination inhibited both. Inhibition of several oncogenes, including FOXM1, associated with poor prognosis and aggressive HCC, was identified by both single treatments and the combination. FOXM1-overexpressed stable clones were generated to evaluate the role of FOXM1 in treatment efficacy. FOXM1 stable clones showed a stronger resistance to cell death, and increases in migration and invasion in the presence of treatment. Studies are ongoing to evaluate in vivo therapeutic efficacy and further elucidate the mechanism FOXM1’s downregulation.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-5-2026