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Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer

Award Number: F31CA247417
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/10/2019
PERIOD OF PERFORMANCE END DATE: 12/09/2022

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Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer - Project Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$2,316 )
2024	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	3	10/31/2023	NON-COMPETING CONTINUATION	-$2,316
														Subtotal = -$2,316

Issue Date FY: 2022 ( Subtotal = $34,052 )
2022	2022	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	3	12/3/2021	NON-COMPETING CONTINUATION	$33,336
2022	2022	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	3	6/1/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $34,052

Issue Date FY: 2021 ( Subtotal = $33,336 )
2021	2021	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	2	12/9/2020	NON-COMPETING CONTINUATION	$32,820
2021	2021	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	2	2/3/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $33,336

Issue Date FY: 2020 ( Subtotal = $32,820 )
2020	2020	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	1	12/3/2019	NEW	$32,316
2020	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	002	1	2/11/2020	NEW	$504
2020	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	1	12/3/2019	NEW	$0
														Subtotal = $32,820

Grand Total All Awards = $97,892

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Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer

Award Number: F31CA247417

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/10/2019

PERIOD OF PERFORMANCE END DATE: 12/09/2022

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