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Targeting Atg5 in platinum-resistant ovarian cancer

Award Number: R21CA249376
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Targeting Atg5 in platinum-resistant ovarian cancer - Abstract Ovarian cancer is the fifth leading cause of cancer-related death in the United States. The standard first line chemotherapy to treat this deadly disease includes platinum (cisplatin/carboplatin)-based treatment, but the development of drug resistance presents a significant clinical problem that needs to be addressed. Our current study identifies a novel mechanism of cisplatin resistance involving autophagy-related gene (Atg) 5. Atg5 is a member of the Atg family that plays an important role in regulating autophagy, a process essential for the quality control of cellular components under various stress conditions. Previous studies showed that the inhibition of autophagy sensitizes cancer cells to chemotherapy. Our own study showed that the blockade of autophagy induction promotes cisplatin sensitivity in human ovarian cancer cells, but strategies for targeting autophagy in cancer therapies in general are not well developed. We find that Atg5 is overexpressed in human ovarian tumors, and that its overexpression inhibits cisplatin-induced apoptosis in ovarian cancer cells. We also find that Atg5 overexpression is correlated with the poor overall survival in ovarian cancer patients treated with platinum-based chemotherapy. Additionally, we find that Atg5 is phosphorylated but the effects of its phosphorylation on Atg5-mediated autophagy and cisplatin resistance remain to be determined. Based on these novel observations, we hypothesize that elevated Atg5 expression confers growth advantage of ovarian cancer cells by promoting cell survival and drug resistance. The objectives of this project are to define the role of Atg5 in cisplatin resistance and the impact of Atg5 phosphorylation on cisplatin resistance. These objectives will be achieved by the following two Specific Aims: 1) Define the role of Atg5 in cisplatin resistance both in vitro and in vivo using ovarian cancer mouse models; and 2) Determine the regulation of Atg5 phosphorylation and its impact on cisplatin resistance. Successful results from this study could lead to the development of novel therapeutic strategies for treating ovarian cancer patients.


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	2022	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	000	2	5/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $211,665 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	000	2	12/6/2021	NON-COMPETING CONTINUATION	$194,386
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	001	2	6/7/2022	NON-COMPETING CONTINUATION	$17,279
														Subtotal = $211,665

Issue Date FY: 2021 ( Subtotal = $179,988 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	000	1	11/23/2020	NEW	$179,988
														Subtotal = $179,988

Grand Total All Awards = $391,653

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Targeting Atg5 in platinum-resistant ovarian cancer

Award Number: R21CA249376

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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