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Reversing Resistance to PARP-Inhibitor in Triple Negative Breast Cancer

Award Number: SC3GM122655
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Reversing Resistance to PARP-Inhibitor in Triple Negative Breast Cancer - Of the several subtypes of breast cancer, the hormone-refractory `triple negative breast cancer (TNBC)' (indicating lack of estrogen, progesterone and HER2neu receptor expression) are less responsive to treatment and have a much worse prognosis as compared to receptor-positive breast cancer. The five-year survival rate for TNBC is 77% versus 93% of women with other types of breast cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are emerging as promising therapeutics for the treatment of TNBC in a clinical setting. However, acquired resistance to PARPi presents a pervasive barrier to effective treatment and the underlying mechanisms of resistance are poorly understood which has substantiated a need for further investigation in the mechanisms of resistance to PARPi. Autophagy is a self-digestive process, wherein in response to environmental stress, misfolded and aggregated proteins are sequestered and delivered to the lysosome for subsequent degradation and recycling. These recycled biomolecules resulting from autophagy, provide the rapidly growing tumor cells a steady stream of nutrients. Many clinical studies have implemented an autophagy inhibitor (AI) in combination with other drugs to elicit effective cell death in multiple cancers including breast cancer. Autophagy inhibition has also shown to reverse the resistant phenotype of several cancers. Perplexingly, while autophagy inhibition in combination with other chemotherapeutic agents has shown promising therapeutic potential in TNBCs, no major advances have been made in understanding the molecular mechanisms underlying autophagy in resistance to PARPi in TNBCs. Within the scope of this proposal, we address an unmet pressing need to evaluate the synergistic effect of AI in combination with PARPi in the reversal of TNBC resistance to PARPi. Current research proposal is aimed at improving our understanding of the molecular mechanisms of autophagy-apoptosis crosstalk in conferring resistance to PARPi in TNBC. Our main objectives are: 1) Using a combinatorial treatment of autophagy inhibitor (AI) with PARPi, characterize the modulation of apoptotic and autophagic markers in cell death and 2) Identify and evaluate the important rate-limiting factors such as LC3, Akt and oxidative stress involved in modulating autophagy and apoptosis in the resistant TNBC model. The results and contributions of this study will be significant and innovative as they can provide novel avenues for pharmacological intervention in overcoming resistance to PARPi and change the treatment paradigm for this subset of breast cancer with poor prognosis and limited treatment options.


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 = -$129,561 )
2023	2020	HAMPTON UNIVERSITY	200 WILLIAM R HARVEY WAY	HAMPTON	VA	23668	HAMPTON CITY	USA	Biomedical Research and Research Training	001	4	7/18/2023	NON-COMPETING CONTINUATION	-$111,000
2023	2019	HAMPTON UNIVERSITY	200 WILLIAM R HARVEY WAY	HAMPTON	VA	23668	HAMPTON CITY	USA	Biomedical Research and Research Training	000	3	7/18/2023	NON-COMPETING CONTINUATION	-$18,561
														Subtotal = -$129,561

Issue Date FY: 2020 ( Subtotal = $111,000 )
2020	2020	HAMPTON UNIVERSITY	200 WILLIAM R HARVEY WAY	HAMPTON	VA	23668	HAMPTON CITY	USA	Biomedical Research and Research Training	000	4	9/2/2020	NON-COMPETING CONTINUATION	$111,000
														Subtotal = $111,000

Issue Date FY: 2019 ( Subtotal = $111,000 )
2019	2019	HAMPTON UNIVERSITY	100 E QUEEN ST	HAMPTON	VA	23668	HAMPTON CITY	USA	Biomedical Research and Research Training	000	3	8/28/2019	NON-COMPETING CONTINUATION	$111,000
														Subtotal = $111,000

Issue Date FY: 2018 ( Subtotal = $111,000 )
2018	2018	HAMPTON UNIVERSITY	100 E QUEEN ST	HAMPTON	VA	23668	HAMPTON CITY	USA	Biomedical Research and Research Training	000	2	8/31/2018	NON-COMPETING CONTINUATION	$111,000
														Subtotal = $111,000

Issue Date FY: 2017 ( Subtotal = $111,000 )
2017	2017	HAMPTON UNIVERSITY	100 E QUEEN ST	HAMPTON	VA	23668	HAMPTON CITY	USA	Biomedical Research and Research Training	000	1	9/11/2017	NEW	$111,000
														Subtotal = $111,000

Grand Total All Awards = $314,439

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Reversing Resistance to PARP-Inhibitor in Triple Negative Breast Cancer

Award Number: SC3GM122655

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/11/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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