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Novel role of APOBEC3 enzymes as key mediators of cisplatin sensitivity through aberrant processing of interstrand crosslinks

Award Number: R01CA229535
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Cisplatin has been used clinically to treat a variety of cancers for nearly four decades. Along with second and third generation platinum analogs, it is still one of the most widely used chemotherapeutic drugs with over four billion dollars in annual sales. Despite its wide use, clinical limitations including drug toxicity to normal cells and the development of drug resistance in cancers has limited the impact on cancer treatment. Understanding how to overcome these clinical limitations is critical for achieving better cancer responses and increasing overall patient survival. To this end, we have established a novel mechanistic model in which two specific DNA repair pathways, base excision repair (BER) and mismatch repair (MMR), work in conjunction to mediate cisplatin efficacy. This mechanistic model is based on the specific cis/carboplatin DNA interstrand crosslink (ICL) structure in which extrahelical cytosines that flank the ICL are targets for deamination. In this proposal, we have novel preliminary data that supports a family of proteins, APOBEC3 cytidine deaminases, in initiating the deamination of the extrahelical cytosines adjacent to the cisplatin ICLs and activating the BER pathway. Following deamination of the cytosines to uracil, the BER pathway is initiated by uracil DNA glycosylase (UNG) cleavage to produce an abasic site that is subsequently processed by AP endonuclease (APE1) to cleave the phosphodiester backbone adjacent to the cisplatin ICL. Polymerase beta (Polß) is recruited to the 3'-OH site and synthesizes DNA downstream of the cisplatin ICL, but with poor fidelity. We were the first to demonstrate a dependence on Polß nucleotide misincorporation to activate MMR, which ultimately inhibits productive ICL DNA repair and maintains cisplatin sensitivity. In our preliminary data, we demonstrate a dependence on APOBEC3 expression to mediate cis/carboplatin sensitivity and activate the BER response. This is further supported by clinical data in which high APOBEC3 expression can mediate a clinical response to cisplatin. We also demonstrate that mutations in Polß that affect polymerase activity result in hypersensitivity to cisplatin as a consequence of enhanced inhibition of ICL DNA repair. This suggests that the clinically relevant mutations in Polß, which have been observed in ~30% of tumors tested, that alter polymerase function (e.g., decreased catalytic activity and/or decreased fidelity) may be beneficial for better clinical response to cis/carboplatin treatment as a result of the futile processing of cis/carboplatin ICLs. Here, we propose to (i) elucidate the APOBEC3 family members involved in cisplatin sensitivity and ICL cytosine deamination, (ii) assess the interplay between APOBEC3 members and BER/MMR proteins in cisplatin ICL processing and (iii) identify clinical Polß mutations that mediate cisplatin efficacy and determine the dependence on APOBEC3 activity. Therefore, this project will provide a comprehensive mechanistic model for how APOBEC3 proteins activate BER/MMR to maintain cis/carboplatin efficacy and help establish a new paradigm in cis/carboplatin chemotherapy utilizing specific Polß mutations and altered APOBEC3 expression for patient stratification.


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 = $328,060 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	6	3/18/2024	NON-COMPETING CONTINUATION	$310,794
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	6	4/16/2024	NON-COMPETING CONTINUATION	$17,266
														Subtotal = $328,060

Issue Date FY: 2023 ( Subtotal = $21,409 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	5	4/25/2023	NON-COMPETING CONTINUATION	$21,409
2023	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	4	10/27/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $21,409

Issue Date FY: 2022 ( Subtotal = $366,732 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	4	5/2/2022	NON-COMPETING CONTINUATION	$366,732
														Subtotal = $366,732

Issue Date FY: 2021 ( Subtotal = $410,873 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	3	3/9/2021	NON-COMPETING CONTINUATION	$410,873
														Subtotal = $410,873

Issue Date FY: 2020 ( Subtotal = $410,873 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	2	3/13/2020	NON-COMPETING CONTINUATION	$410,873
														Subtotal = $410,873

Issue Date FY: 2019 ( Subtotal = $424,373 )
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	1	1/24/2019	NEW	$424,373
														Subtotal = $424,373

Grand Total All Awards = $1,962,320

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Novel role of APOBEC3 enzymes as key mediators of cisplatin sensitivity through aberrant processing of interstrand crosslinks

Award Number: R01CA229535

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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