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Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis

Award Number: R01CA208834
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis - PROJECT SUMMARY Colorectal cancer (CRC) is the third most prevalent form of cancer in the US and the second leading cause of cancer deaths. Studies over the last several decades have revealed that the gut microbiota influences CRC, and recent work has implicated gut bacterial genotoxins as key effectors in cancer development and progression. One of the bacterial genotoxins most strongly connected to cancer is colibactin, a metabolite produced by human gut commensal bacteria, including certain E. coli strains, that possess a biosynthetic gene cluster termed the pks island. The increased prevalence of pks+ E. coli in CRC patients and the ability of pks+ strains to potentiate tumorigenesis in mouse models of CRC suggest colibactin may play a causal role in cancer progression. However, achieving a mechanistic understanding of colibactin's genotoxicity and contribution to CRC has been impeded by an inability to isolate and structurally characterize the active genotoxic metabolite(s). During the previous funding period of this grant, we gained critical information about colibactin's structure and mode of action by studying the enzymes involved in its biosynthesis. Most notably, we established that colibactin is a DNA alkylating agent and proposed a potential structure for the active genotoxin. The overall objective of this renewal application is to elucidate additional molecular mechanisms underlying colibactin's activity and role in CRC carcinogenesis. Building off of the central hypothesis that the genotoxic activity of colibactin derives from the formation of DNA interstrand cross-links (ICLs), our three specific aims will: 1) characterize the specificity and structure of colibactin-DNA ICLs; 2) develop small molecules that inhibit colibactin biosynthesis in microbial communities; 3) elucidate the physiological location and timing of colibactin-mediated DNA damage in CRC development. These advances will be enabled by our multidisciplinary approach, which merges knowledge and techniques from chemical biology, structural biology, microbiology, toxicology, and cancer biology. Overall, this effort will fill critical gaps in fundamental knowledge needed to elucidate the role of colibactin-producing gut bacteria in CRC carcinogenesis and ultimately impact cancer prevention, diagnosis, and treatment. Additionally, by successfully demonstrating that studying and manipulating individual disease-associated microbial pathways can provide key mechanistic insights, this work will also support and validate future efforts to understand how other gut microbial activities influence CRC initiation and development.


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: 2025 ( Subtotal = $349,441 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	10	9/1/2025	NON-COMPETING CONTINUATION	$349,441
														Subtotal = $349,441

Issue Date FY: 2024 ( Subtotal = $332,015 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	9	7/2/2024	NON-COMPETING CONTINUATION	$332,015
														Subtotal = $332,015

Issue Date FY: 2023 ( Subtotal = $343,119 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	8	7/28/2023	NON-COMPETING CONTINUATION	$343,119
														Subtotal = $343,119

Issue Date FY: 2022 ( Subtotal = $343,161 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	002	7	7/20/2022	NON-COMPETING CONTINUATION	$343,161
2022	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	001	6	10/29/2021	COMPETING CONTINUATION	$215,507
2022	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	10/29/2021	NON-COMPETING CONTINUATION	-$215,507
														Subtotal = $343,161

Issue Date FY: 2021 ( Subtotal = $384,345 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	6	7/29/2021	COMPETING CONTINUATION	$384,345
														Subtotal = $384,345

Issue Date FY: 2020 ( Subtotal = $383,288 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	6/12/2020	NON-COMPETING CONTINUATION	$383,288
														Subtotal = $383,288

Issue Date FY: 2019 ( Subtotal = $371,692 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	4	6/20/2019	NON-COMPETING CONTINUATION	$371,692
														Subtotal = $371,692

Issue Date FY: 2018 ( Subtotal = $383,091 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	3	6/11/2018	NON-COMPETING CONTINUATION	$383,091
														Subtotal = $383,091

Issue Date FY: 2017 ( Subtotal = $382,769 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	2	6/20/2017	NON-COMPETING CONTINUATION	$382,769
														Subtotal = $382,769

Issue Date FY: 2016 ( Subtotal = $398,238 )
2016	2016	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	1	6/9/2016	NEW	$398,238
														Subtotal = $398,238

Grand Total All Awards = $3,671,159

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Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis

Award Number: R01CA208834

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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