Date of Award
2026
Document Type
Dissertation
Degree Name
Pharmaceutical Sciences (Ph.D.)
Department
Pharmaceutical Sciences
First Advisor
Vikas Dukhande
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a deadly solid malignancy, has a 5-year survival rate of 13%. Severe metastasis, acquired drug resistance, rapid growth, late diagnosis, and lack of surgical opportunities due to advanced metastatic progression are hallmarks of this cancer, accounting for poor patient prognosis. Therapies such as cyclin-dependent kinases 4/6 (CDK4/6) and Histone deacetylase (HDAC) inhibitors often fail in clinical trials due to the heterogeneity and acquired resistance during long-term clinical treatment regimens. Altered metabolic reprogramming, aberrant cell cycle progression, and deregulated epigenetics are attractive targets for developing novel therapeutic combinations for PDAC. Our study aimed to investigate the mechanistic effectiveness of a novel combination of Abemaciclib (Abe) and Panobinostat (Pan), for the PDAC. Our cell viability, cell proliferation, and 3D spheroid results demonstrated that the combination was synergistic in inhibiting PDAC cell proliferation and growth. Our protein expression and caspase-3 enzyme assays showed that the combination induced apoptosis as the mechanism of cell death in PDAC. Next, we focused on deciphering the mechanistic events leading to the synergy between the combination in MIA PaCa-2 cells. Our RNA-seq results showed that genes involved in autophagy were upregulated with Pan, which could be due to a cellular stress response to the drug. Metabolomics revealed a decrease in amino acid metabolism following Pan treatment alone. Our western blot data depicted an increase in the autophagy pathway with Pan treatment. On the other hand, RNA-seq and metabolomics data suggested that Abe treatment increased mitochondrial and lysosomal dysfunction. Our Seahorse analysis demonstrated that Abe reduced oxygen consumption, leading to reduced cellular energy production. Interestingly, we observed that Abe, in combination, lowered the autophagy increased by Pan treatment alone, thereby inducing autophagic blockade and eventually cell death. Additionally, we observed that in the xenograft studies the combination was effective at reducing tumor growth and proliferation without adverse effects on body weight. Collectively, our findings suggest that the Abe and Pan combination is effective in combating the deadly PDAC by altering metabolism and inducing autophagic arrest, leading to cell death. Additional research is warranted to investigate the molecular mechanisms underlying the combination-induced autophagic dysfunction in PDAC.
Recommended Citation
Bhutkar, Shraddha Padmakar, "PANOBINOSTAT AND ABEMACICLIB COMBINATION IS EFFECTIVE AND INDUCES METABOLIC ALTERATIONS AND IMPAIRS AUTOPHAGY IN PANCREATIC DUCTAL ADENOCARCINOMA" (2026). Theses and Dissertations. 1126.
https://scholar.stjohns.edu/theses_dissertations/1126