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FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma

Award Number: R01CA222649
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma - Project summary/Abstract The long-term goal of this project is to improve therapeutic options for patients with cholangiocarcinoma by better understanding the pathways that drive disease and increase resistance to therapy. Worldwide, liver cancer is now second only to lung cancer for cancer- related deaths. Cholangiocarcinoma is a primary liver cancer with rising incidence and few effective treatment options. The current project will investigate canonical and non-canonical fibroblast growth factor receptor-4 (FGFR4) signaling in cholangiocarcinoma initiation and progression. Preliminary data demonstrated that cholangiocarcinoma cells exhibited autocrine FGFR4 signaling through expression and secretion of the ligand FGF19. Inhibition of this pathway increased apoptosis and decreased cell growth with effects at the G1/S checkpoint, S phase duration, and mitosis. FGFR4 is strongly expressed in tumor tissue compared to normal bile ducts. FGFR inhibition markedly reduced tumor size in rats and knockdown of FGFR4 prevented subcutaneous tumor formation. We have identified a novel proteolytic cleavage product of the full-length receptor that is composed of the intracellular domain (R4- ICD). R4-ICD contains the C-terminal tyrosine kinase domain, activated AKT, and prevented apoptosis. The central hypothesis of this proposal is that signaling through FGFR4 and R4-ICD drives cholangiocarcinoma initiation, progression, and chemoresistance. Experiments in aim 1 will determine how malignant features are promoted by R4-ICD and FGFR4. Aim 2 will identify tumor-initiating mechanisms of FGFR4 and R4-ICD. The third aim will demonstrate the role FGFR4 and R4-ICD in chemotherapy resistance. Successful completion of this project will increase our understanding of how FGFR4 promotes cholangiocarcinoma progression and resistance to therapy, define new biology of R4-ICD, and test treatment strategies that inhibit FGFR4 processing or kinase activity.


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 = -$324 )
2024	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	5	5/10/2024	NON-COMPETING CONTINUATION	-$324
														Subtotal = -$324

Issue Date FY: 2022 ( Subtotal = $341,335 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	001	5	5/26/2022	NON-COMPETING CONTINUATION	$27,865
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	5	12/14/2021	NON-COMPETING CONTINUATION	$313,470
														Subtotal = $341,335

Issue Date FY: 2021 ( Subtotal = $348,301 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	001	4	1/26/2021	NON-COMPETING CONTINUATION	$17,416
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	4	12/9/2020	NON-COMPETING CONTINUATION	$330,885
														Subtotal = $348,301

Issue Date FY: 2020 ( Subtotal = $348,301 )
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	3	12/6/2019	NON-COMPETING CONTINUATION	$313,470
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	001	3	1/13/2020	NON-COMPETING CONTINUATION	$34,831
														Subtotal = $348,301

Issue Date FY: 2019 ( Subtotal = $337,851 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	2	12/20/2018	NON-COMPETING CONTINUATION	$337,851
														Subtotal = $337,851

Issue Date FY: 2018 ( Subtotal = $346,973 )
2018	2018	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	1	12/27/2017	NEW	$346,973
														Subtotal = $346,973

Grand Total All Awards = $1,722,437

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FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma

Award Number: R01CA222649

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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