# TARGETING TRYPTOPHAN METABOLISM IN COLITIS ASSOCIATED CANCER

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $343,125

## Abstract

   
DESCRIPTION (provided by applicant): Colitis associated cancer (CAC) is a major complication and cause of early death in patients with chronic inflammatory bowel disease. There is an unmet need for new therapies that specifically treat CAC but spare the normal epithelium. We found that indoleamine 2, 3 dioxygenase (IDO1), an enzyme that initiates tryptophan metabolism along the kynurenine pathway (KP), is activated in chronic colitis and promotes CAC development. Our new data identify the colon epithelium as the key IDO1 expressing cell type promoting CAC growth. We also find that kynurenine, the initial IDO1-KP metabolite, activates important transcriptional pathways of colon neoplasia. Finally, we demonstrate that colon neoplastic transformation leads to constitutive activation of IDO1, which in turn promotes growth in a cell-intrinsic manner. Based on these observations, our overarching hypothesis is that "Inhibiting the IDO1-kyurenine pathway in the neoplastic epithelium of established CAC can selectively enhance cytotoxic therapy, while not adding toxicity to the normal epithelium". Our overall goal is to determine how to best target the IDO1-KP as a novel CAC therapy. We propose to address the following questions. Can IDO1 inhibition synergize with cytotoxic CAC therapies to enhance outcomes, but not toxicity? What are the mechanisms by which IDO1 and KP metabolites promote CAC growth and how does the KP affect normal epithelial cells differently than neoplastic? Are there more suitable targets for CAC therapy upstream from IDO1 or within the KP, either with greater efficacy or less toxicity? We will use innovative approaches including intestinal specific IDO1 knockout (IDO-iKO) mice, human organoid culture (tumoroids, colonoids and enteroids), a new IDO1 inhibitor with high potency and specificity, and a unique Biobank of human CAC and colitis-associated dysplasia samples. The significance is that completion of our studies will identify how the IDO1-KP may be targeted as a novel, precision approach to CAC therapy with the goal of limiting toxicity to the normal intestine. As IDO1 is also expressed in a subset of sporadic colorectal cancers (CRC) where it portends a poor prognosis, our findings may also apply beyond CAC.

## Key facts

- **NIH application ID:** 9928046
- **Project number:** 5R01DK109384-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW AARON CIORBA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2016-05-05 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928046

## Citation

> US National Institutes of Health, RePORTER application 9928046, TARGETING TRYPTOPHAN METABOLISM IN COLITIS ASSOCIATED CANCER (5R01DK109384-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928046. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*