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Folic Acid Supplementation and Colitis-associated Colon Carcinogenesis

Award Number: R01CA262551
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/11/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Folic Acid Supplementation and Colitis-associated Colon Carcinogenesis - Project Summary/Abstract Patients with ulcerative colitis, a form of inflammatory bowel disease, face an increased risk of developing colorectal cancer. Although advances have been made in the therapeutic management of this disease, much less attention has been given to the development of cancer preventive strategies for this high-risk population. Ulcerative colitis patients often develop folate deficiencies that require supplementation with folic acid (FA), a synthetic form of folate. The effect of FA on risk for colorectal cancer remains unclear and the recent suggestion that FA supplements may be useful in preventing colitis-associated colorectal cancer is of great concern. Preliminary studies from this group provide the first evidence that FA supplementation (8 mg/kg diet) causes a dose-dependent increase in the formation of colorectal tumors in mice with AOM/DSS-induced colitis. Results from associated RNASeq and in vitro analyses suggest that FA promotes tumorigenesis by activating ERK and inducing NF-κB signaling in colonic epithelial cells with dysfunctional p53, the gatekeeping event in the development of colitis-associated cancers. The hypothesis of the proposed studies is that FA supplementation promotes UC-associated cancer in cells with dysfunctional/mutant p53, but not in cells with wild type p53, via an inflammatory pathway mediated by ERK and NF-κB. The mechanism by which FA induces tumor formation will be investigated in Aim 1 using CRISPR engineered isogenic human RKO colon carcinoma cells with varying p53 status (p53+/+, p53-/- and p53+/Mut). The impact of FA and dysfunctional p53 on activation of ERK, NF-κB signaling, as well as cell cycle progression will be evaluated. In vitro findings will be validated in Aim 2, where complimentary in vivo analyses will examine the combined effect of FA and mutant p53 on DSS-induced colitis-associated tumorigenesis and associated biomarkers in p53+/+ and p53+/515A (mutant) mice. In addition, the impact of high dose FA given prior to the induction of colitis will be examined. Tumor incidence and multiplicity, as well as degree of intestinal inflammation, will serve as primary endpoints of these studies. Based on the important contribution of intestinal microbiota to colitis and their ability to synthesize folate de novo, the impact of FA administration on the diversity and relative abundance of fecal and adherent bacteria within the intestine of p53+/515A mice with DSS-induced colitis will be examined in Aim 3. Mice will be treated with 5-aminosalicylic acid (5-ASA), a common maintenance therapy for ulcerative colitis, for the duration of FA exposure to recapitulate the clinical therapy of a patient following a diagnosis of colitis. The composition of the fecal and colon-adherent microbiomes, determined from 16S rRNA and metagenomic sequencing data, will be correlated with colonic inflammation, barrier function and tumor incidence/multiplicity. The results are expected to provide significant insight into the impact of FA supplementation on colitis-associated tumorigenesis and inform the first guidelines for the use of FA supplements by patients with ulcerative colitis.


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 = $648,814 )
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$64,881
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	$583,933
														Subtotal = $648,814

Issue Date FY: 2024 ( Subtotal = $525,677 )
2024	2024	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	3	4/11/2024	NON-COMPETING CONTINUATION	$525,677
														Subtotal = $525,677

Issue Date FY: 2023 ( Subtotal = $484,469 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	2	4/17/2023	NON-COMPETING CONTINUATION	$484,469
														Subtotal = $484,469

Issue Date FY: 2022 ( Subtotal = $423,946 )
2022	2022	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	1	5/11/2022	NEW	$423,946
														Subtotal = $423,946

Grand Total All Awards = $2,082,906

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Folic Acid Supplementation and Colitis-associated Colon Carcinogenesis

Award Number: R01CA262551

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/11/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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