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Mechanisms of Selective Therapeutic Synergy of PARP-inhibition and CTLA4 Blockade Engaged by Interferon-gamma in the Ovarian Tumor Microenvironment

Award Number: R37CA229221
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract The high mortality rate associated with ovarian cancer results from the failure of tumor-directed therapy to produce lasting treatment responses. Durable survival in patients with other solid tumors has recently been achieved using immune checkpoint antibodies, however similar results have not been observed in women with ovarian cancer. Published work from our lab demonstrates that combining poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPi) with immune checkpoint blockade can achieve long-term survival in ovarian cancer models. The scientific premise for this study is based accumulating evidence of a dynamic interaction between PARPi and the tumor microenvironment (TME) that regulates treatment response and disease outcomes. Work to date has identified a tumor-intrinsic mechanism by which PARPi interact with interferon gamma (IFNg) to promote immunogenic cell death in ovarian cancer cells. This results in activation of tumor immunity in vivo, associated with the successful induction of protective immune memory. Evidence that conditions in the tumor environment significantly modulate the therapeutic efficacy of PARP-inhibitors, termed “contextual synthetic lethality”, presents an opportunity to maximize patient outcomes and target treatment effects to the TME. Here we propose to examine the contribution of PARP trapping by different PARPi on these tumor-intrinsic mechanisms to determine whether we can induce similar results in BRCAwt cancers. We will additionally expand studies of tumor- extrinsic immune modulation by PARPi in the TME to test whether macrophage polarization can engage secondary mechanisms of CTLA4ab to enhance treatment outcomes. Finally we will validate candidate biomarkers of response in patients enrolled in two clinical trials, and will examine associations with immune profiling in collaboration with the Cancer Immune Monitoring Analysis Centers. With the rapid adoption of immune checkpoint antibodies and PARP-inhibitors for the treatment of ovarian cancer and other tumor types, this proposal has potential for immediate clinical impact through current and planned clinical trials.


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 = $316,716 )
2024	2024	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	6	2/27/2024	EXTENSION WITH OR WITHOUT FUNDS	$316,716
														Subtotal = $316,716

Issue Date FY: 2023 ( Subtotal = $342,987 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	5	2/1/2023	NON-COMPETING CONTINUATION	$342,987
														Subtotal = $342,987

Issue Date FY: 2022 ( Subtotal = $349,981 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	001	4	5/24/2022	NON-COMPETING CONTINUATION	$34,999
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	4	1/24/2022	NON-COMPETING CONTINUATION	$314,982
														Subtotal = $349,981

Issue Date FY: 2021 ( Subtotal = $348,835 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	3	1/26/2021	NON-COMPETING CONTINUATION	$348,835
														Subtotal = $348,835

Issue Date FY: 2020 ( Subtotal = $348,832 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	2	2/4/2020	NON-COMPETING CONTINUATION	$348,832
														Subtotal = $348,832

Issue Date FY: 2019 ( Subtotal = $361,703 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	1	2/18/2019	NEW	$361,703
														Subtotal = $361,703

Grand Total All Awards = $2,069,054

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Mechanisms of Selective Therapeutic Synergy of PARP-inhibition and CTLA4 Blockade Engaged by Interferon-gamma in the Ovarian Tumor Microenvironment

Award Number: R37CA229221

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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