# Targeting Tryptophan Metabolism in Rectal Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $633,106

## Abstract

Project Summary/Abstract:
More than 40,000 new rectal cancers occur annually in the US and the majority are locally advanced when
diagnosed (LARC). Current total neoadjuvant therapy (TNT) with chemoradiation followed by surgery provides
modest outcomes with a 20-25% pathologic complete response (pCR) rate and 5-year disease survival of only
65%. Therefore, there is an unmet need for new treatment approaches that improve LARC clinical outcomes
and reduce morbidity. Using LARC patient samples and pre-clinical modeling, we recently identified a rationale
for combining short course radiation therapy (SCRT) with inhibitors of the immuno-oncology target IDO1.
Indoleamine 2,3 dioxygenase 1 (IDO1) metabolizes tryptophan along the kynurenine pathway and is recognized
as a potent suppressor of tumor reactive immunity. Our robust findings identify IDO1 overexpression as a
pathologic response in LARC therapy leading to immune-independent treatment resistance and an
immunosuppressive TME. We found that: 1) Radiation induces IDO1 overexpression universally across LARC
patients and in colorectal cancer (CRC) models regardless of MSI status. 2) IDO1 activity directly promotes
critical mediators of CRC growth and treatment resistance (β-catenin and PI3K/AKT; 3) In mice, the potent IDO1
inhibitor epacadostat (EPA) sensitizes CRC to simulated SCRT radiation by relieving immune suppression and
augmenting radiation induced CRC apoptosis. We have conducted a Phase I dose escalation study of
epacadostat in combination with SCRT/chemotherapy, and identified EPA 400mg BID to be safe and shows
preliminary evidence of efficacy. These findings lead us to conclude with following central hypothesis: IDO1
inhibition is a rationally selected adjunctive immunotherapy in CRC that enhances anti-tumor immunity,
synergizes with DNA damaging therapy, and protects the normal small intestine. Project goals include:
Defining efficacy of EPA/SCRT/chemotherapy as TNT for LARC and a pharmacodynamic basis for EPA in a
biospecimen accruing Phase II trial with a randomized biomarker cohort (Aim 1). Defining biomarkers and
identifying precision medicine approaches to support the further clinical study of this combination (Aim 2). We
will leverage institutional experience and expertise, our established clinical trial infrastructure (NCT03516708),
and a standard-of-care cohort, to address this central hypothesis Impact: If successful, we will take this
approach to a potentially practice-changing, randomized phase III clinical trial using precision medicine
approaches to address the unmet need to improve LARC patient outcomes. As IDO1 is also upregulated in
other solid tumors treated by RT (cervix, anal, etc), the approach of combining EPA with genotoxic therapies
might be expanded to other solid tumor types.

## Key facts

- **NIH application ID:** 10932926
- **Project number:** 5R01CA278197-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW AARON CIORBA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $633,106
- **Award type:** 5
- **Project period:** 2023-09-21 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932926

## Citation

> US National Institutes of Health, RePORTER application 10932926, Targeting Tryptophan Metabolism in Rectal Cancer (5R01CA278197-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10932926. Licensed CC0.

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