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Identifying determinants of ADAR-dependency in triple-negative breast cancer

Award Number: R00MD016946
ORGANIZATION: NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Identifying determinants of ADAR-dependency in triple-negative breast cancer - PROJECT SUMMARY Triple-negative breast cancer (TNBC), the deadliest form of breast cancer, affects Black/African American women at twice the rate of white women. Additionally, the survival rate for TNBC is lower in Black/African women. To address the disparities associated with TNBC we need broadly applicable targeted therapies. Without targeted therapies, clinicians are left with chemotherapy, which has many negative side- effects and in many cases is ultimately ineffective in the treatment of TNBC. We have observed that a subset of TNBC cell lines are dependent on the expression of Adenosine Deaminase Acting on RNA (ADAR). ADAR is an enzyme that converts adenosine nucleotides in RNA to inosine in a process known as A-to-I editing. Loss of ADAR inhibits cellular proliferation and tumor formation for a subset of TNBC cell lines. Because ADAR is required for the growth of some TNBC cell lines it serves as a valuable therapeutic target for the treatment of TNBC. It has been observed that ADAR-dependent cell lines have elevated interferon signaling, potentially making it possible to classify ADAR-dependent tumors. Interferon signaling is higher in Black/African American breast tumors than tumors in white patients, which may make therapies targeting ADAR more effective for Black/African American patients. There are aspects of ADAR-dependence that we do not understand. For instance, we do not understand why some cells are dependent on ADAR expression while others are not. Here we will explore the mechanism of ADAR-dependency and develop a strategy for treatment of TNBC based on ADAR inhibition. In AIM 1 we will identify the factors that are required for ADAR-dependence, including identification of the immunogenic RNAs that contribute to the phenotype caused by ADAR depletion. In AIM 2 we will develop and assess a classification model to predict which tumors will be sensitive to ADAR inhibition. The accuracy of the classification model will be evaluated by knockdown of ADAR in patient derived xenograft models of TNBC. Importantly this AIM will provide the PI with training in mouse models of breast cancer, including tumor implantation and monitoring. Finally, in AIM 3, we will develop a high-throughput A-to-I editing assay and use it to identify a small molecule inhibitor of ADAR. In addition to the potential identification of a small molecule inhibitor of ADAR, this AIM will provide the PI with experience developing a high-throughput screen and the use of DNA-encoded chemical libraries. This work will advance our understanding of ADAR- dependency such that we can accurately classify ADAR-dependent TNBC, thus opening the door to treating this deadly form of breast cancer with the small molecules identified in AIM 3. Developing an effective targeted therapy for TNBC is essential to reducing the disparate effects of this disease on Black/African American women. Finally, the research and career development training included in this grant will facilitate the PIs transition into an independent investigator.


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: 2025 ( Subtotal = $224,101 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	001	5	4/29/2025	NON-COMPETING CONTINUATION	$0
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	000	5	12/13/2024	NON-COMPETING CONTINUATION	$224,101
														Subtotal = $224,101

Issue Date FY: 2024 ( Subtotal = $249,000 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	000	4	12/9/2023	NON-COMPETING CONTINUATION	$224,101
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	001	4	5/31/2024	NON-COMPETING CONTINUATION	$24,899
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $249,640 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	000	3	12/18/2022	EXTENSION WITH OR WITHOUT FUNDS	$224,100
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	001	3	1/30/2023	EXTENSION WITH OR WITHOUT FUNDS	$24,900
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Minority Health and Health Disparities Research	002	3	8/29/2023	EXTENSION WITH OR WITHOUT FUNDS	$640
														Subtotal = $249,640

Grand Total All Awards = $722,741

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Identifying determinants of ADAR-dependency in triple-negative breast cancer

Award Number: R00MD016946

ORGANIZATION: NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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