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Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation

Award Number: P01CA160032
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1997
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation - DNA alkylating agents, including nitrogen mustards (NM) such as cyclophosphamide (CPA), remain in heavy use as anti-cancer agents. They are employed in adjuvant chemotherapy regimens, such as the AC (anthracycline-CPA) therapy frequently administered to breast cancer patients. The primary site of alkylation in DNA is the N7-guanine position. This Program focuses upon chemistry and biology that happens after N7-dG alkylation: the NM N7-alkylated guanines undergo interstrand cross-link formation (ICL), base-induced ring-opening, yielding stable alkyl-formamidopyrimidine (N5-substituted-Fapy) lesions, and depurination, yielding apurinic (AP) sites. These types of complex DNA damage are may contribute substantially to the mechanisms of action of NM agents, including cytoxicity. Knowledge of the spectrum of complex DNA damage created by NM agents during therapy and the biological processing of this damage is critical for the design of effective treatment regimens. We have shown that the anthracyline antibiotic doxorubicin (Adriamycin), a component of AC therapy, forms covalent conjugates with AP sites, a previously unrecognized activity for this drug. Thus, AP sites formed as a consequence of NM treatment or as base excision repair (BER) intermediates provide targets for adjuvant therapies designed to increase cytotoxicity. Complex DNA damage arising from rearrangement of N7-dG alkylation sites has until now been understudied, in part, due to an inability to rigorously prepare DNAs containing such damage for biological, biochemical, and structural studies. Insights gained from our Program will yield fundamental and applied understanding of complex DNA damage arising from DNA alkylation and its detection in cellular DNA, innovative syntheses for the production and characterization of DNAs containing site-specific complex damage, structural understanding of how complex damage and AP site conjugation products alters DNA structure, and modulates repair and replication, effective design of anthracycline analogs targeted to AP sites, new biomarkers and analytical methods with which to monitor real time therapeutic efficacy in patients undergoing chemotherapy, and improved adjuvant therapy regimens designed to maximize cytotoxic response in cancer vs normal cells.


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 = $0 )
2026	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	000	30	12/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	000	30	7/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $1,406,557 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	000	30	7/12/2022	NON-COMPETING CONTINUATION	$1,406,557
														Subtotal = $1,406,557

Issue Date FY: 2021 ( Subtotal = $1,435,785 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	000	29	8/19/2021	NON-COMPETING CONTINUATION	$1,435,785
														Subtotal = $1,435,785

Issue Date FY: 2020 ( Subtotal = $1,435,936 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	000	28	7/21/2020	NON-COMPETING CONTINUATION	$1,435,936
														Subtotal = $1,435,936

Issue Date FY: 2019 ( Subtotal = $1,389,474 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	002	27	7/24/2019	NON-COMPETING CONTINUATION	$1,389,474
2019	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	001	26	12/14/2018	COMPETING CONTINUATION	$147,882
2019	2016	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Cause and Prevention Research	000	25	12/14/2018	EXTENSION WITH OR WITHOUT FUNDS	-$147,882
														Subtotal = $1,389,474

Issue Date FY: 2018 ( Subtotal = $1,457,333 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Cause and Prevention Research	002	26	9/19/2018	COMPETING CONTINUATION	$1,457,333
2018	2016	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Cause and Prevention Research	001	25	9/14/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Cause and Prevention Research	000	25	8/1/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $1,457,333

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Cause and Prevention Research	001	25	3/7/2017	EXTENSION WITH OR WITHOUT FUNDS	$885,891
2017	2015	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Cause and Prevention Research	000	24	3/7/2017	NON-COMPETING CONTINUATION	-$885,891
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $1,398,429 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Cause and Prevention Research	000	25	7/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$1,398,429
														Subtotal = $1,398,429

Issue Date FY: 2015 ( Subtotal = $1,398,429 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Cause and Prevention Research	000	24	7/20/2015	NON-COMPETING CONTINUATION	$1,398,429
														Subtotal = $1,398,429

Issue Date FY: 2014 ( Subtotal = $1,356,477 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Cause and Prevention Research	000	23	8/1/2014	NON-COMPETING CONTINUATION	$1,356,477
														Subtotal = $1,356,477

Issue Date FY: 2013 ( Subtotal = $1,314,524 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Cause and Prevention Research	000	22	7/16/2013	NON-COMPETING CONTINUATION	$1,314,524
														Subtotal = $1,314,524

Issue Date FY: 2012 ( Subtotal = $1,426,429 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Cause and Prevention Research	000	21	9/20/2012	COMPETING CONTINUATION	$1,426,429
														Subtotal = $1,426,429

Grand Total All Awards = $14,019,373

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Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation

Award Number: P01CA160032

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1997

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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