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Targeting DNA Repair for Cancer Therapy.

Award Number: R35CA197574
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2032

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Targeting DNA Repair for Cancer Therapy. - This R35 renewal application seeks to identify and exploit tumor-specific vulnerabilities based on DNA repair deficiencies and to develop novel therapeutic strategies that specifically target tumors. In the recent funding period, we discovered that elevated levels of the oncometabolites 2-hydroxyglutarate (2HG), fumarate, and succinate in human cancers inhibit homology-dependent repair (HDR) by disrupting chromatin signaling at DNA double strand breaks (DSBs), conferring a previously unsuspected vulnerability to PARP inhibitors (PARPi). These oncometabolites are over-produced in human malignancies with mutations in isocitrate dehydrogenase- 1 and -2 (IDH1/2), fumarate hydratase (FH), and succinate dehydrogenase (SDH). Our work, published in Nature, Nature Genetics, and Science Translational Medicine, has led to seven new clinical trials testing a new therapeutic paradigm of treating these tumors with PARPi, with promising initial results. In this renewal, we propose to further elucidate fundamental mechanisms underlying the DNA repair deficiency in oncometabolite- producing cells, with a focus on chromatin remodelers and DNA end-protection factors, prompted by new data from RNA-sequencing analyses. We will also probe potential pathways of PARPi resistance and develop strategies to overcome them. Approaches will include comprehensive analyses of DNA repair and chromatin regulation, unbiased CRISPR screens, and small molecule drug screens. We have also demonstrated tumor-specific targeting by peptide-drug conjugates via a pH-sensitive peptide (pHLIP) that exploits tumor acidity, with a pHLIP-exatecan conjugate that we developed now in a Phase 1 trial. Based on our pre-clinical work that established specific delivery to tumors with sparing of bone marrow, we propose to develop new pHLIP-small molecule conjugates that inhibit the DNA repair factor, DNA-PK, to selectively radiosensitize tumors while sparing healthy tissue. We will perform tumor efficacy and normal tissue toxicity studies with a goal of advancing a tumor-specific radiosensitizing agent for clinical translation. We have also produced a novel version of our cell-penetrating and tumor targeting antibody (designated V66, a humanized 3E10 variant). With this antibody, we will test a new hypothesis that we can exploit intracellular antibody/antigen clearance pathways to develop bispecific antibodies as selective protein degraders, combining a V66 arm (for its tumor targeting and cell penetration properties) with a second antibody arm specific for binding to an intracellular factor. This work could provide a new class of cell-penetrating, proteolysis targeting antibodies (PROTABs) to degrade otherwise undruggable intracellular factors for cancer therapy. Importantly, we have now obtained key proof-of-concept data that we can achieve targeted protein degradation of GFP by treatment of cells with a newly generated V66/anti-GFP bispecific antibody. This work spans from foundational basic science to pre-clinical animal tumor work, with potential for clinical translation, and so is well suited to the broader scope of the R35 funding mechanism.


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: 2026 ( Subtotal = $906,075 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	9	2/5/2026	NON-COMPETING CONTINUATION	$906,075
														Subtotal = $906,075

Issue Date FY: 2025 ( Subtotal = $1,004,999 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	001	8	1/21/2025	COMPETING CONTINUATION	$945,000
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	002	8	1/28/2025	COMPETING CONTINUATION	$60,000
2025	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	7	11/18/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = $1,004,999

Issue Date FY: 2023 ( Subtotal = $982,379 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	7	7/18/2023	NON-COMPETING CONTINUATION	$982,379
														Subtotal = $982,379

Issue Date FY: 2022 ( Subtotal = $984,900 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	6	8/26/2022	NON-COMPETING CONTINUATION	$984,900
														Subtotal = $984,900

Issue Date FY: 2021 ( Subtotal = $1,004,920 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	5	7/26/2021	NON-COMPETING CONTINUATION	$1,004,920
														Subtotal = $1,004,920

Issue Date FY: 2020 ( Subtotal = $1,004,921 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	4	6/29/2020	NON-COMPETING CONTINUATION	$1,004,921
														Subtotal = $1,004,921

Issue Date FY: 2019 ( Subtotal = $880,502 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	3	7/22/2019	NON-COMPETING CONTINUATION	$880,502
														Subtotal = $880,502

Issue Date FY: 2018 ( Subtotal = $1,005,000 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	2	7/20/2018	NON-COMPETING CONTINUATION	$1,005,000
														Subtotal = $1,005,000

Issue Date FY: 2017 ( Subtotal = $773,292 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	1	7/25/2017	NEW	$773,292
														Subtotal = $773,292

Grand Total All Awards = $8,546,988

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Targeting DNA Repair for Cancer Therapy.

Award Number: R35CA197574

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2032

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