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MiRNAs in hepatocellular carcinoma development and treatment

Award Number: R01CA139158
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/25/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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MiRNAs in hepatocellular carcinoma development and treatment - Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver and the third leading cause of death from cancer. However, currently there is no effective treatment for HCC. It is therefore urgent to develop novel therapeutic approaches for the treatment of HCC. Increasing evidence suggests that being able to modulate specific miRNAs may lead to the development of novel cancer therapies. Our studies (and others) indicate that a microRNA, miR-26a, represses proinflammatory cytokines, especially interleukin 6 (IL-6) and its downstream mediator, signal transducer and activator of transcription 3 (STAT3), suggesting a tumor suppressive role of miR-26a on HCC development. However, the role of miR-26a in HCC development in the setting consisting of both hepatocytes and Kupffer cells in appropriate HCC mouse models has not been determined. Furthermore, whether modulating miR-26a in hepatocytes and/or Kupffer cells can be an effective therapeutic approach for treating HCC has not been tested. The objective of this proposal is to investigate the molecular and cellular mechanisms by which miR-26a overexpression in hepatocytes and Kupffer cells inhibits HCC development. In addition, we have identified small molecules and developed siRNA/RNA in vivo targeted delivery technology that can increase miR-26a expression in the liver. In Aim 1, we will determine the effect of overexpression of miR-26a in hepatocytes and in Kupffer cells on suppression of HCC development. We have generated hepatocyte-specific as well as Kupffer cell-specific miR-26a overexpression transgenic mice. We will use these unique transgenic mouse lines to define the cellular and molecular mechanisms by which miR-26a exerts its effect on HCC. In Aim 2, we will determine the effect of small molecules on miR-26a induction and HCC suppression. We have also developed an innovative siRNA/RNA in vivo targeted delivery technology-- CpG-siRNA/RNA—that enables RNA in vivo delivery into Toll-like Receptor 9-positive Kupffer cells and inflammatory/malignant hepatocytes. CpG-Stat3 siRNA is moving towards clinical trials for glioma and lymphoma patients at City of Hope. We will assess the effect of both CpG-miR-26a and CpG-Stat3 siRNA on HCC development in hepatocytes or/and Kupffer cells in animal models. The proposed studies will not only provide mechanistic insights into pathways underlying HCC but also help to develop effective treatment strategies for HCC.


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 = $0 )
2024	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	10	1/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $410,875 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	10	5/6/2021	NON-COMPETING CONTINUATION	$410,875
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	9	2/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $410,875

Issue Date FY: 2020 ( Subtotal = $410,875 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	9	1/14/2020	NON-COMPETING CONTINUATION	$41,088
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	9	12/12/2019	NON-COMPETING CONTINUATION	$369,787
														Subtotal = $410,875

Issue Date FY: 2019 ( Subtotal = $398,548 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	8	12/12/2018	NON-COMPETING CONTINUATION	$398,548
														Subtotal = $398,548

Issue Date FY: 2018 ( Subtotal = $410,875 )
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	7	12/11/2017	NON-COMPETING CONTINUATION	$369,787
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	7	5/22/2018	NON-COMPETING CONTINUATION	$41,088
														Subtotal = $410,875

Issue Date FY: 2017 ( Subtotal = $410,874 )
2017	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	6	1/16/2017	COMPETING CONTINUATION	$410,875
2017	2015	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	5	5/1/2017	NON-COMPETING CONTINUATION	-$1
														Subtotal = $410,874

Issue Date FY: 2015 ( Subtotal = $344,450 )
2015	2015	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	5	1/26/2015	NON-COMPETING CONTINUATION	$34,445
2015	2015	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	11/25/2014	NON-COMPETING CONTINUATION	$310,005
														Subtotal = $344,450

Issue Date FY: 2014 ( Subtotal = $334,117 )
2014	2014	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	12/13/2013	NON-COMPETING CONTINUATION	$310,005
2014	2014	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	4	4/16/2014	NON-COMPETING CONTINUATION	$24,112
														Subtotal = $334,117

Issue Date FY: 2013 ( Subtotal = $323,783 )
2013	2013	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	3	6/6/2013	NON-COMPETING CONTINUATION	$151,558
2013	2013	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	12/17/2012	NON-COMPETING CONTINUATION	$172,225
														Subtotal = $323,783

Issue Date FY: 2012 ( Subtotal = $344,450 )
2012	2012	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	12/30/2011	NON-COMPETING CONTINUATION	$310,005
2012	2012	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	2	4/26/2012	NON-COMPETING CONTINUATION	$34,445
														Subtotal = $344,450

Issue Date FY: 2011 ( Subtotal = $344,450 )
2011	2011	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	1/25/2011	NEW	$344,450
														Subtotal = $344,450

Grand Total All Awards = $3,733,297

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MiRNAs in hepatocellular carcinoma development and treatment

Award Number: R01CA139158

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/25/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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