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Mechanisms of APOBEC3A-induced cancer evolution and cancer vulnerability

Award Number: R01CA262874
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/09/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Mechanisms of APOBEC3A-induced cancer evolution and cancer vulnerability - PROJECT SUMMARY/ABSTRACT Cancer evolution driven by DNA-mutating APOBEC enzymes (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like), and the emergence of resistance to therapy, present a pressing clinical challenge. In particular, the APOBEC3A (A3A) enzyme is implicated in a range of cancers and is hypothesized to drive resistance to targeted anticancer therapies. This project proposes to explore the mechanisms of A3A activity during targeted therapy, its substrate preferences, and potential methods of inhibiting its activity to slow cancer evolution and impede the emergence of drug resistance. Aim 1 focuses on investigating the role of A3A in the emergence of drug resistance, hypothesizing that A3A expression is upregulated during targeted therapy, leading to APOBEC- signature mutations. We will test this using lung cancer cell-line models and targeted therapies, and will use CRISPR technology to genetically eliminate A3A and monitor the impact on the emergence of drug-resistant cells. Aim 2 seeks to determine the genomic, transcriptomic, and proteomic targets of A3A and other APOBECs. Our previous work suggests that APOBEC mutagenesis and RNA editing are directed by local and mesoscale structural constraints. We will conduct computational analyses to identify hotspots of A3A activity in DNA and RNA and their subsequent protein effects, refining our understanding of APOBEC mutagenesis and identifying super-optimal A3A substrates. Aim 3 proposes to evaluate the efficacy of hairpins and hairpin-like molecules as A3A inhibitors. We anticipate that A3A's affinity for hairpin substrates may render it susceptible to inhibition by hairpins or hairpin-like molecules. Testing will be performed in vitro and in cells to assess whether hairpin molecules can inhibit endogenous cellular A3A activity and slow drug resistance evolution. Through a combination of computational and experimental approaches, this research will advance our understanding of APOBEC mutagenesis, potentially offering novel diagnostics, research tools, and treatments for APOBEC-driven 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 = $530,113 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	4/9/2026	NON-COMPETING CONTINUATION	$530,113
														Subtotal = $530,113

Issue Date FY: 2025 ( Subtotal = $531,759 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	3/31/2025	NON-COMPETING CONTINUATION	$478,582
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	001	2	5/23/2025	NON-COMPETING CONTINUATION	$53,177
														Subtotal = $531,759

Issue Date FY: 2024 ( Subtotal = $545,288 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	4/8/2024	NEW	$545,288
														Subtotal = $545,288

Grand Total All Awards = $1,607,160

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Mechanisms of APOBEC3A-induced cancer evolution and cancer vulnerability

Award Number: R01CA262874

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/09/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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