# Genetics-guided Individualization of Thiopurine Therapy

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $549,331

## Abstract

Abstract
Thiopurines (e.g., mercaptopurine [MP]) are highly effective against hematologic malignancies (leukemia and
lymphoma) and autoimmune diseases (inflammatory bowel diseases [IBD]). In acute lymphoblastic leukemia
(ALL) in particular, prolonged daily exposure to MP is indispensable for the cure of this cancer. However,
thiopurines have narrow therapeutic indexes with dose-limiting hematopoietic toxicity that causes extensive
morbidity, disruption of treatment, and possible mortality. Therefore, there is enormous clinical benefit from
preemptively identifying patients at risk of thiopurine toxicity and individualizing therapy to mitigate it. Thiopurine
toxicity is also highly influenced by inherited genetic variations, particularly polymorphisms in the TPMT gene
as discovered by our group and others. Recently, we reported a novel variant in the NUDT15 gene that lead to
its loss of nucleotide diphosphatase activity, excessive levels of active thiopurine metabolite, dramatic increase
in MP-induced apoptosis and severe toxicity in patients (J Clin Oncol 2015 and unpublished preliminary
results).
Because the low activity NUDT15 allele alters the metabolism of thiopurines, we hypothesize that we can
rationally reduce thiopurine dose in patients who inherit the NUDT15 variants and tailor their exposure to
thiopurine active metabolite TGTP to the level comparable to wildtype patients receiving conventional doses,
similar to the principle of TPMT-guided thiopurine dose reduction. To test this hypothesis, we propose three
specific aims to 1) comprehensively identify MP toxicity-related NUDT15 and
TPMT
ALL (N=1,028), 2) characterize the effects of NUDT15 and
characterize how NUDT15 and variants influence thiopurine disposition in children with ALL (N=1,550),
TPMT
variants
 variants in children with
on its function, and finally 3)
TPMT
from which to develop a NUDT15-/TPMT-based pharmacogenetic algorithm for MP dose adjustments.
Successful completion of these studies is likely to establish a novel precision medicine paradigm for thiopurine
therapy to proactively individualize dose before toxicity occurs. We are confident that this highly translational
project will likely have immediate impact on the treatment of ALL, and our findings can be readily extrapolated
to thiopurine therapy for non-malignant conditions (e.g., IBD) thus impact a large number of patients.

## Key facts

- **NIH application ID:** 9828095
- **Project number:** 5R01GM118578-04
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Jun J. Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,331
- **Award type:** 5
- **Project period:** 2017-01-09 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828095

## Citation

> US National Institutes of Health, RePORTER application 9828095, Genetics-guided Individualization of Thiopurine Therapy (5R01GM118578-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828095. Licensed CC0.

---

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