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Targeting the DNA damage response in combination with radiation to induce innate immunity and improve immunotherapy efficacy in pancreatic cancer

Award Number: R01CA240515
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Targeting the DNA damage response in combination with radiation to induce innate immunity and improve immunotherapy efficacy in pancreatic cancer - ABSTRACT Therapeutic strategies are needed to improve the efficacy of immune checkpoint blockade (ICB) therapy in pancreatic ductal adenocarcinomas (PDAC). PDACs have an increased reliance on the DNA damage response (DDR) for mitigating oncogene-induced replication stress and, the DDR regulates innate immunity via regulation of cGAS/STING/TBK1-mediated detection of cancer DNA. ATM is the apical kinase in the DDR and the target of small molecule inhibitors in clinical development. Furthermore, ionizing radiation stimulates the cGAS/STING/TBK1 innate immune pathway to modulate immune responses in a type 1 interferon (T1IFN)- dependent fashion that are required for the synergy of radiation with ICB. Therefore, the central hypothesis of this proposal is that a novel direct link between ATM and innate immune sensing pathways can be leveraged therapeutically in combination with radiation to enhance the tumoral T1IFN pathway and improve ICB efficacy in otherwise poorly immunogenic PDACs. This hypothesis will be tested in three specific aims: Aim 1 will define the immunologic consequences of ATM inhibition in combination with radiation and the mechanisms by which ATM affects innate immunity in PDAC. In this aim we will assess the contributions of cytoplasmic DNA (1A), ATM substrates (1B), and pattern recognition receptor pathway signaling (1C) to immune endpoints such as T1IFN-mediated signaling, PD-L1 expression, and T cell-mediated killing (1D). Aim 2 will investigate the immune contribution to the sensitivity of ATM depleted PDAC tumors to the combination of radiation and PD-L1 therapy. Our preliminary data suggest that ATM has both tumor and host immune-dependent mechanisms (i.e. T1IFN secretion) that influence the sensitivity of tumors to combined anti-PD-L1 and radiation. We will determine the contribution of tumoral and host T1IFN signaling to the sensitivity of ATM-deficient tumors to combined anti-PD-L1 and radiation therapy (2A) as well as the immune consequences (2B). We hypothesize that the therapeutic advantages of ATM deficiency will be diminished in T1IFNR deficient tumor cells and hosts since tumoral T1IFN production likely increases tumor immunosurveillance through both tumor and host-dependent mechanisms. In Aim 3 we will develop a therapeutic strategy combining ATM inhibitors and radiation with anti-PD-L1 in PDAC. Our preliminary data show that pharmacologic ATM inhibition activates the immune pathway. We will determine the efficacy of the clinical candidate ATM inhibitor AZD0156 in combination with anti-PD-L1 and the optimal radiation dose/fractionation schema in syngeneic PDAC tumors and autochthonous PDAC tumors in genetically engineered mouse models (3A). We will also develop pharmacodynamic biomarkers that will be predictive of the therapeutic efficacy of ATM inhibition and radiation in combination with anti-PD-L1 (3B). Completion of these aims will define a new connection between ATM, radiation and innate immunity that will be leveraged therapeutically to extend the efficacy of ICB to PDAC which is highly relevant to the mission of the NIH.


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 = $430,481 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	5	4/23/2024	NON-COMPETING CONTINUATION	$430,481
														Subtotal = $430,481

Issue Date FY: 2023 ( Subtotal = $443,233 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	4	2/28/2023	NON-COMPETING CONTINUATION	$443,233
														Subtotal = $443,233

Issue Date FY: 2022 ( Subtotal = $443,233 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	3	2/16/2022	NON-COMPETING CONTINUATION	$407,046
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	001	3	5/3/2022	NON-COMPETING CONTINUATION	$36,187
														Subtotal = $443,233

Issue Date FY: 2021 ( Subtotal = $452,277 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	2	2/15/2021	NON-COMPETING CONTINUATION	$452,277
														Subtotal = $452,277

Issue Date FY: 2020 ( Subtotal = $452,277 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	1	2/20/2020	NEW	$452,277
														Subtotal = $452,277

Grand Total All Awards = $2,221,501

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Targeting the DNA damage response in combination with radiation to induce innate immunity and improve immunotherapy efficacy in pancreatic cancer

Award Number: R01CA240515

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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