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NOX4 Mediates Oxidative Stress in Ovarian Tumor growth and treatment Response

Award Number: R01CA193511
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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NOX4 Mediates Oxidative Stress in Ovarian Tumor growth and treatment Response - DESCRIPTION (provided by applicant): Ovarian cancer represents the fifth leading cause of cancer-related death among women. However, the mechanisms of ovarian cancer development and its response to treatment remain to be elucidated. Our preliminary results show that ovarian cancer cells generate higher levels of reactive oxygen species (ROS) through NOX4 overexpression compared to immortalized normal ovary epithelial cells. Knockdown of NOX4 in cancer cells decreased ROS production, as well as expression of HER2, HER3 and ATG14. To test how NOX4 is upregulated in ovarian cancer cells, we find that HIF-1 and p70S6K1 are activated in these cells. It is known that HIF-1 and p70S6K1 are activated by oncogenes, such as PI3K and Ras, and by mutations of tumor suppressors, such as PTEN and p53. Our preliminary results indicate that HIF-1 and p70S6K1 induce NOX4 overexpression. We hypothesize that HIF-1 and p70S6K1 induce NOX4 overexpression, which in turn induces HER2/HER3 co-expression and ATG14 expression through miR-199a/miR-152 suppression, leading to ovarian tumor growth, angiogenesis, and therapeutic resistance. We will use multidisciplinary approaches, including molecular biology, animal models and human cancer tissue analysis, to test our hypothesis through three specific aims. Aim 1 will determine whether HIF-1 and p70S6K1 induce NOX4 expression, which in turn mediates HER2 and HER3 co-expression; whether NOX4 regulates trastuzumab treatment resistance through HER2 and HER3, and regulates radiation treatment resistance through induction of autophagy and ATG14 expression. We will manipulate expression of HIF-1, p70S6K1, NOX4 and other molecules in the cells and define the roles of these molecules in trastuzumab and radiation treatment responses. Aim 2 will determine whether NOX4 induces ovarian tumor growth through HER2 and HER3 co-expression via miR-199a suppression using an orthotopic ovarian tumor model, and determine whether NOX4 affects radiation treatment effect via ATG14 using image-guided radiotherapy. Aim 3 will determine whether NOX4 regulates tumor angiogenesis through HER2, HER3, and miR-199a suppression; and investigate whether levels of NOX4, ROS, HER2, HER3, miR-199a, and miR-152 correlate with advanced ovarian cancer stages and survival. Taken together, these results obtained from this application will establish a novel molecular mechanism of NOX4 signaling in regulating ovarian cancer development and provide proof- of-principle as to how NOX4 regulates radiation and trastuzumab treatment resistance. These results will provide the basis for designing a new therapeutic approach by targeting NOX4, HER2/HER3 co-expression, and/or ATG14 for ovarian cancer therapy. These studies will also provide new biomarker(s) using higher levels of NOX4, ROS, ATG14, and/or HER2/HER3 co-expression to predict advanced ovarian cancer stages, radiation or/and trastuzumab treatment resistance in the future.


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 = -$824 )
2024	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	7	1/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$824
														Subtotal = -$824

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	7	10/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	7	12/17/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$30,597
2022	2019	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	5	12/17/2021	NON-COMPETING CONTINUATION	-$30,597
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	6	1/12/2021	NON-COMPETING CONTINUATION	-$321,204
2021	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	7	1/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$321,204
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $321,204 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	6	7/23/2020	NON-COMPETING CONTINUATION	$321,204
														Subtotal = $321,204

Issue Date FY: 2019 ( Subtotal = $305,098 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	5	5/24/2019	NON-COMPETING CONTINUATION	$305,098
														Subtotal = $305,098

Issue Date FY: 2018 ( Subtotal = $321,204 )
2018	2018	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	004	4	5/2/2018	NON-COMPETING CONTINUATION	$321,204
2018	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	2	3/9/2018	NON-COMPETING CONTINUATION	-$250,878
2018	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	002	2	4/24/2018	NON-COMPETING CONTINUATION	-$23,123
2018	2017	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	003	3	4/24/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$23,123
2018	2017	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	001	3	3/9/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$250,878
														Subtotal = $321,204

Issue Date FY: 2017 ( Subtotal = $356,850 )
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	2	11/9/2016	NON-COMPETING CONTINUATION	$321,165
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$35,685
														Subtotal = $356,850

Issue Date FY: 2016 ( Subtotal = $356,850 )
2016	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	1	11/27/2015	NEW	$356,850
														Subtotal = $356,850

Grand Total All Awards = $1,660,382

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NOX4 Mediates Oxidative Stress in Ovarian Tumor growth and treatment Response

Award Number: R01CA193511

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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