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Combined breast MRI/biomarker strategies to identify aggressive biology

Award Number: U01CA189283
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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Combined breast MRI/biomarker strategies to identify aggressive biology - DESCRIPTION (provided by applicant): Triple-negative breast cancers [ER (-)/PR (-)/HER2wt (TNBC)] are highly aggressive breast cancers that frequently occur in BRCA1 mutation carriers and young women of African origin (AA). While Ashkenazi women with TNBC have a 60% incidence of germline BRCA1 mutation, less than 40% of Caucasian and only 20% of AA women with TNBC carry a germline BRCA1 mutation. We discovered a novel tumor suppressor gene, WW domain-containing oxidoreductase (WWOX) and observe that loss of WWOX activates glycolysis and glucose uptake. In this proposal, we aim to investigate the role of WWOX signaling in activating metabolism in TNBC. In preliminary data, we observe Wwox-deficient cells exhibit increased HIF1a and activity and display increased glucose uptake. WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, consistent with the 'Warburg effect'. Based on our preliminary data, we hypothesize that WWOX controls glycolytic genes' expression through regulation of HIF1a. In pilot studies, we tested for loss of WWOX expression and FLIM metabolic imaging in human breast tissue. We observe that WWOX expression is lost in 88% of TNBC, and in all AA women we tested. In these preliminary studies we observed that loss of WWOX expression correlated high glycolytic metabolic signatures in both non-cancerous tissue from high-risk and in TNBC. Taken together these studies highlight a potential role for the tumor suppressor WWOX in activating glycolysis and cellular metabolism during cancer initiation. Here we aim to test from the bench to the clinic the hypothesis that loss of the tumor suppressor WWOX 1) in preclinical models mechanistically activates of glycolysis in metastatic TNBC via transcriptional activation HIF1a and 2) in primary and metastatic TNBC activates metabolism as measured by Fluorescence Lifetime Imaging (FLIM). Aim 1 will test whether loss of WWOX in TNBC activate glycolysis by transcriptional activation of HIF1a. Aim 2 will investigate whether loss of WWOX expression predicts increased metabolism/glycolysis during progression and metastasis of TNBC.


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: 2023 ( Subtotal = -$262,535 )
2023	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	6	5/19/2023	NON-COMPETING CONTINUATION	-$262,535
														Subtotal = -$262,535

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	6	8/16/2021	NON-COMPETING CONTINUATION	$0
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	6	4/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $492,629 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	6	7/29/2020	NON-COMPETING CONTINUATION	$649,862
2020	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	002	5	8/18/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	4	4/27/2020	NON-COMPETING CONTINUATION	-$157,233
														Subtotal = $492,629

Issue Date FY: 2019 ( Subtotal = $992,415 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	002	5	7/23/2019	NON-COMPETING CONTINUATION	$656,559
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	003	5	9/5/2019	SUPPLEMENT FOR EXPANSION	$178,623
2019	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	4	7/17/2019	NON-COMPETING CONTINUATION	$157,233
2019	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	4	2/20/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $992,415

Issue Date FY: 2018 ( Subtotal = $854,044 )
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	4	7/26/2018	NON-COMPETING CONTINUATION	$663,841
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	4	8/1/2018	SUPPLEMENT FOR EXPANSION	$190,203
														Subtotal = $854,044

Issue Date FY: 2017 ( Subtotal = $885,212 )
2017	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	3	9/13/2017	SUPPLEMENT FOR EXPANSION	$190,203
2017	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	3	9/1/2017	NON-COMPETING CONTINUATION	$695,009
														Subtotal = $885,212

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2015	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	002	2	8/24/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2016	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cancer Detection and Diagnosis Research	001	1	4/22/2016	NEW	-$698,567
2016	2015	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	2	4/22/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$698,567
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $742,866 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cancer Detection and Diagnosis Research	000	1	7/31/2015	NEW	$742,866
														Subtotal = $742,866

Grand Total All Awards = $3,704,631

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Combined breast MRI/biomarker strategies to identify aggressive biology

Award Number: U01CA189283

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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