# Development of Drug Detoxifying Bacteria for Chemotherapy Induced Gut Injury

> **NIH NIH R41** · SANARENTERO LLC · 2021 · $399,955

## Abstract

PROJECT SUMMARY/ ABSTRACT
Irinotecan-based chemotherapy is widely used for the treatment of various types of metastatic cancers, however,
severe drug-induced injury or gastrointestinal (GI) toxicity, especially severe delayed-onset diarrhea (SDOD)
induced by SN-38 (an active metabolite of irinotecan), limits its clinical application of the drug. Irinotecan-induced
SDOD incidences result in increased healthcare cost due to hospitalization, and poor quality of life and
therapeutic outcomes for the cancer patients. Currently, there is no effective treatment available for about ~15%
of patients receiving irinotecan therapy, who suffer unmanageable SDOD symptoms, mainly due to their inability
to detoxify the SN-38 in the colon. SN-38 mediated intestinal toxicity was found to be more severe in patients
with uridine diphosphate glycosyltransferases 1A1 (UGT1A1) polymorphism, delineating the critical role of
colonic UGT1A1 in the prevention of SN-38 induced SDOD. Various approaches to reduce SN-38 colonic
exposure has been tried without much success, and SDOD remains unmanageable dose-limiting toxicity of
irinotecan in adult and pediatric cancer patients. Preliminary research of our academic research collaborators at
the University of North Texas and the University of Houston discovered glucosyltransferases from plant
Medicago truncatula that could efficiently metabolize typical human UGT1A1 substrates, including SN-38, in an
in vitro assay. This led to the novel and innovative concept of bioengineering commensal bacteria E.coli (EC) for
overexpressing plant UGT71G1 to create a drug detoxifying bacteria (DDB) that can detoxify SN-38. In this STTR
project, we propose to generate proof-of-concept preclinical evidence in support of developing a safe,
efficacious, and traceable DDB as a novel live biotherapeutic product (LBP) to alleviate and/or prevent the SN-
38-mediated intestinal toxicity. Here, we will bioengineer a commensal E.coli strain, with good human gut
colonization potential, to overexpress the most active variant of UGT71G1 (U71G1*n) tagged with a green
fluorescent protein (GFP), which will be delivered in a protective capsule directly to the colon for the effective
glycosylation of SN-38 to SN-38-glucose. To achieve this goal, the proposed specific aims are 1) to develop
traceable and more active drug detoxifying bacteria EC_U71G1*n (active variant) to detoxify SN-38, 2) to
develop a colon-optimized capsule delivery of traceable and highly active lyophilized DDBs, and 3) to evaluate
the efficacy of 2 colon-delivered DDBs in irinotecan induced SDOD rat model. An active DDB engineered with
pUGT biocatalyst (for the detoxification of SN-38) and GFP (for tracing the effective gut colonization in human
feces for therapeutic efficacy monitoring) will accelerate the recovery of cancer patients from SDOD, and lead to
the effective management of irinotecan-induced SDOD in clinics. The success of this project will provide
Sanarentero with the proof-of-c...

## Key facts

- **NIH application ID:** 10252721
- **Project number:** 1R41CA261292-01
- **Recipient organization:** SANARENTERO LLC
- **Principal Investigator:** MING HU
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,955
- **Award type:** 1
- **Project period:** 2021-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10252721

## Citation

> US National Institutes of Health, RePORTER application 10252721, Development of Drug Detoxifying Bacteria for Chemotherapy Induced Gut Injury (1R41CA261292-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10252721. Licensed CC0.

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