Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal neoplasm in the US with 5- year-survival rate of 8.5%. Currently, gemcitabine single agent or combination chemotherapies remain the most commonly used frontline treatment for locally invasive and metastatic PDAC. However, most PDAC tumors are intrinsically resistant or quickly acquire resistance to gemcitabine. Epigenetic reprogramming through changes in global DNA methylation or histone modification have been implicated in chemoresistance. Here, I established a model for gemcitabine resistance progression in PDAC and identified a cytostatic transition phase prior to regrowth under gemcitabine treatment. Through a small-molecule epigenetic inhibitor screen, I identified PRMT1 (H4R3 arginine methyltransferase) and KMT2A/B (H3K4 lysine methyltransferase) as positive and negative regulators of transition into gemcitabine resistance, respectively. Based on these findings, I hypothesize that PDAC cells transition into gemcitabine resistance through epigenetic reprogramming that is in part mediated by PRMT1 and KMT2A/B.
In Aim 1, I will functionally validate PRMT1 and KMT2A/B in modulating PC gemcitabine resistance in vitro and in vivo.
In Aim 2, I will investigate the mechanisms by which PRMT1 and KMT2A/B modulate gemcitabine resistance through integrated genomic analysis. Collectively, I expect my study will shed important new insight into the mechanisms of gemcitabine resistance in PDAC, which could lead to novel combination therapies to enhance the efficacies and durability of gemcitabine in PDAC.

Public Health Relevance

Understanding how pancreatic cancer evades therapy is essential for combating this deadly disease. Epigenetic reprogramming has emerged as an important mechanism of disease progression and therapy resistance in human pancreatic cancer patients. Here, I will specifically investigate the role of epigenetic reprogramming in the development of resistance to gemcitabine - the most commonly used chemotherapy drug for pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA247417-02
Application #
10071870
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2019-12-10
Project End
2022-12-09
Budget Start
2020-12-10
Budget End
2021-12-09
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057