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Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

Award Number: R01CA243511
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer - Poly ADP ribose polymerase inhibitors (PARPi) have shown extraordinary clinical benefits in the treatment of BRCA mutant homologous recombination (HR) deficient ovarian cancer. A critical clinical problem is chemotherapy drugs, including PARPi, are far less effective in BRCA wild-type HR proficient, poor prognostic ovarian cancer (e.g. CCNE1 amplification/gain). Combining PARPi with other drugs is an emerging strategy to overcome this problem. The PI has shown epigenetic drugs, histone deacetylase inhibitors (HDACi), bromodomain extra-terminal inhibitors (BETi), and DNA methyltransferase inhibitors (DNMTi), enhance PARPi efficacy in preclinical models of HR proficient ovarian cancer. Epigenetic drugs primarily activate or repress gene transcription in a cell type- and context-dependent manner. In the context of CCNE1 amplified/gain HR proficient ovarian cancer, the PI has demonstrated chemically diverse epigenetic drugs induce a “BRCA mutant-like” contextual synthetic lethal phenotype, characterized by repressed HR gene expression and function. The overall objective of this proposal is to determine if the extraordinary benefits of PARPi therapy can be extended through rational PARPi-epigenetic drug combinations for a new indication in BRCA wild-type HR proficient, poor prognostic ovarian cancer. Even with extensive published and preliminary results from the PI's group and others, gaps in knowledge remain regarding optimal PARPi-epigenetic regimens for clinical use, appropriate biomarkers of response, and precise underlying mechanisms of action. To address these gaps, we will apply a translational research approach that takes full advantage of our collective expertise including: unique primary cell lines and patient-derived xenograft (PDX) preclinical models, clinical patient biosamples associated with an approved phase 1/2 trial, and state-of-the-art genome-wide strategies. As a result, we are perfectly positioned to test the central hypothesis that epigenetic drugs enhance PARPi efficacy in BRCA wild-type HR proficient ovarian cancer by inducing a BRCA mutant-like phenotype through repression of common HR transcriptional targets and contextual synthetic lethality. The Specific Aims are designed to determine the therapeutic potential of new PARPi-epigenetic drug regimens in preclinical models of ovarian cancer, to investigate HR deficient status as a surrogate biomarker of a new PARPi-epigenetic drug regimen in clinical development, and to elucidate mechanisms of response to PARPi-epigenetic drug regimens in HR proficient ovarian cancer cells using genome-wide strategies. This innovative translational approach has high potential for advancing new preclinical PARPi-epigenetic drug regimens to the clinic, along with new biomarkers as companion diagnostics, and new mechanistic insights for both PARPi and epigenetic drugs. As a result, the proposed studies will have broad implications beyond ovarian cancer. Because a critical clinical problem is the lack of effective treatment options for BRCA wild-type HR proficient tumors, establishing benefits of PARPi-epigenetic therapy for this typically poor prognostic ovarian cancer has the potential for high impact.


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 = $518,225 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	001	6	5/24/2024	SUPPLEMENT FOR EXPANSION	$105,398
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	6	4/15/2024	NON-COMPETING CONTINUATION	$412,827
														Subtotal = $518,225

Issue Date FY: 2023 ( Subtotal = $555,311 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	5	2/25/2023	SUPPLEMENT FOR EXPANSION	$109,193
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	5	2/24/2023	NON-COMPETING CONTINUATION	$446,118
														Subtotal = $555,311

Issue Date FY: 2022 ( Subtotal = $493,473 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	4	5/19/2022	NON-COMPETING CONTINUATION	$34,616
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	002	4	9/6/2022	SUPPLEMENT FOR EXPANSION	$69,487
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	4	2/22/2022	NON-COMPETING CONTINUATION	$389,370
														Subtotal = $493,473

Issue Date FY: 2021 ( Subtotal = $446,882 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	002	3	3/2/2021	NON-COMPETING CONTINUATION	$446,882
2021	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Cancer Treatment Research	000	1	12/3/2020	NEW	-$76,784
2021	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	2	12/3/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$76,784
														Subtotal = $446,882

Issue Date FY: 2020 ( Subtotal = $445,360 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	002	2	8/31/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$322,610
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Cancer Treatment Research	000	1	3/2/2020	NEW	$454,054
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Cancer Treatment Research	001	1	8/31/2020	NEW	-$331,304
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	003	2	9/1/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $445,360

Grand Total All Awards = $2,459,251

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Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

Award Number: R01CA243511

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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