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Simultaneous ROS production and DDR inhibition to trigger p53 synthetic lethality

Award Number: R01CA285616
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/11/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Simultaneous ROS production and DDR inhibition to trigger p53 synthetic lethality - PROJECT SUMMARY/ABSTRACT Anti-cancer drugs that target cancer-specific events are expected to cause minimal damage in normal tissues, resulting in significantly reduced side effects. Deficiency in the tumor suppressor p53 gene by gene mutations or deletions are detected in ~50% of human cancers, one of the most frequent cancer-specific events. The goal of this proposal is to identify a strategy and novel compounds that efficiently induce cell death specifically in cancer cells deficient in p53, known as “p53 synthetic lethality”. Similar compounds or drugs have been under development; however, their efficacy is not robust and has not yet been clinically proven. This is mainly due to poor understanding of mechanisms that induce p53 synthetic lethality, context-dependent specificity, and low efficacy of identified compounds. Our recent high-throughput screen has identified a compound, called “KU”, that specifically induces DNA damage, mitotic arrest, and cell death in various p53-deleted or -mutated osteosarcoma (OS) cells with minimal effects on non-tumor cells carrying intact p53. “KU” induces reactive oxygen species (ROS) production and inhibits ATM phosphorylation. We have also identified that deuterated and/or fluorinated KU analogs, called KU-D2 and KU-D2F, respectively, have much higher cytotoxic activities with increased specificity to p53 deficiency, as compared to KU. Our hypothesis is that KU analogs (KU-D2, KU-D2F) induce mitotic arrest and cell death specifically in p53-deficient cells as a single agent through the dual effects of causing ROS-mediated DNA double-strand breaks (DSBs) and inhibiting ATM-mediated DNA damage response (DDR), offering an efficient and unique strategy to induce p53 synthetic lethality. Aim 1 is to determine requirement of ROS (not by other chemotherapy drugs)-mediated DSBs and DDR inhibition for efficient induction of p53 synthetic lethality, phenocopying the effects of KU analogs. We will show that simultaneous induction of ROS- mediated DSBs and inhibition of DDR phenocopy the mechanism of action of KU analogs, leading to efficient induction of p53 synthetic lethality. We will also identify and validate proteins binding to KU analogs involved in the observed biological phenotypes. Aim 2 will determine in vivo toxicity/safety and pharmacological properties of KU-D2 and KU-D2F, as well as the in vivo effects of these compounds on tumor suppression in orthotopic (allo- and xeno-grafts) and patient-derived xenografts (PDXs) OS mouse models. We will also show that simultaneous treatment of both a ROS inducer and an ATM inhibitor can selectively inhibit growth of p53-deficient tumors and whether overexpression of potential KU analog-target proteins, including NBS1 and PRDX3, rescues the in vivo tumor suppressive effects of KU-D2F. Thus, this study reveals that p53-deficiet cells are vulnerable to simultaneous treatment of ROS-mediated DSB induction and DDR inhibition, which is an efficient strategy to induce p53 synthetic lethality. We will also identify novel compounds that efficiently induce p53 synthetic lethality as a single agent by targeting vulnerabilities imposed by p53 deficiency, which could be employed to develop novel anti-cancer therapies to treat p53-deficient cancers.


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 = $545,708 )
2026	2026	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Cancer Treatment Research	000	2	2/27/2026	NON-COMPETING CONTINUATION	$545,708
														Subtotal = $545,708

Issue Date FY: 2025 ( Subtotal = $560,458 )
2025	2025	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Cancer Treatment Research	000	1	3/11/2025	NEW	$560,458
														Subtotal = $560,458

Grand Total All Awards = $1,106,166

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Simultaneous ROS production and DDR inhibition to trigger p53 synthetic lethality

Award Number: R01CA285616

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/11/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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