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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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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 with immune checkpoint blockade can achieve long- term survival in ovarian cancer models. Early results from an ongoing clinical trial have now demonstrated significant clinical efficacy of this regimen in women with recurrent ovarian cancer. Here we propose to dissect the mechanisms responsible for the observed therapeutic synergy of this combination to enable the optimal integration of immune therapy with cytotoxic regimens for long-term benefit in women with ovarian cancer. The scientific premise for this study is based accumulating evidence of a dynamic interaction between tumor cells and the tumor microenvironment (TME) that regulates treatment response and disease outcomes. Our work additionally demonstrates that the TME interacts directly with tumor- targeted agents to enhance tumor clearance. Combined PARP-inhibition and CTLA4 blockade resulted in a significant increase in the proportion of T cells producing IFN¿ in the TME, an effect which persisted long after completion of therapy. We found that IFN¿ enhanced tumor cytotoxicity in response to PARP- inhibition through a cell-intrinsic mechanism in vitro, and that IFN¿ was required for the survival benefit observed in vivo. 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 dissect the cell-intrinsic and –extrinsic mechanisms responsible for the observed therapeutic synergy of PARP inhibitors and CTLA4 blockade and to develop a treatment predictive biomarker linked to these mechanisms for clinical translation. 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: 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


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


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


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


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


Grand Total All Awards = $1,752,338

Sum of Action Amount is $1,752,338;

Grand Total = $1,752,338

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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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