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CYCLOOXYGENASE-2 SIGNALING IN CELL SENESCENCE AND ITS ROLE IN CHEMOTHERAPY-INDUCED LONG-TERM ADVERSE SEQUELAE

Award Number: R15CA246429
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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CYCLOOXYGENASE-2 SIGNALING IN CELL SENESCENCE AND ITS ROLE IN CHEMOTHERAPY-INDUCED LONG-TERM ADVERSE SEQUELAE - PROJECT SUMMARY Survivors of childhood cancer are often associated with adverse, late-onset side effects of earlier cancer treatments, which can be severe or even life-threatening. However, the underlying mechanisms of therapy- induced late effects in this growing population are not known. We developed a novel mouse model for the late effects of chemotherapy, in which juvenile exposure to doxorubicin (DOX) results in tissue accumulation of senescent cells in adult mice and persistent up-regulation of cyclooxygenase-2 (COX2), a key enzyme in prostanoid synthesis. Using this model, we found that treatment with aspirin, a COX inhibitor, following juvenile exposure to DOX improved the long-term adverse effects and reduced the levels of senescent markers in adult mice. Additionally, we have recently reported that inducible expression of COX2 in adult transgenic mice led to increased senescence and a panel of early-aging phenotypes. Given the suggested role of cellular senescence in side effects of chemotherapy, we hypothesize that COX2 plays an important role in chemotherapy-induced senescence and that targeting the prostanoid signaling can effectively suppress senescence. Specific Aim 1 will establish COX2 as a mediator of chemotherapy-induced senescence using a novel mouse model and define its mechanism. In Specific Aim 2, we aim to identify the prostanoid signaling as a better and more selective therapeutic target for cellular senescence. Completion of the proposed research will identify potential treatment strategies to prevent the long-term adverse effects of childhood cancer therapies, which will lead to a higher quality of survivorship. At the same time, it could provide a novel insight into the role of COX2 in normal and pathological aging processes.


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 = -$23,662 )
2024	2020	MIDWESTERN UNIVERSITY	19555 N. 59TH AVE ADMINISTRATION BUILDING	GLENDALE	AZ	85308	MARICOPA	USA	Cancer Treatment Research	000	1	4/11/2024	NEW	-$23,662
														Subtotal = -$23,662

Issue Date FY: 2020 ( Subtotal = $450,000 )
2020	2020	MIDWESTERN UNIVERSITY	19555 N 59TH AVE	GLENDALE	AZ	85308	MARICOPA	USA	Cancer Treatment Research	000	1	11/29/2019	NEW	$450,000
														Subtotal = $450,000

Grand Total All Awards = $426,338

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CYCLOOXYGENASE-2 SIGNALING IN CELL SENESCENCE AND ITS ROLE IN CHEMOTHERAPY-INDUCED LONG-TERM ADVERSE SEQUELAE

Award Number: R15CA246429

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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