# Modeling Vincristine-Induced Severe and Persistent Neuropathy

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2020 · $176,175

## Abstract

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a devastating and often lifelong adverse drug reaction
associated with standard of care chemotherapy for many pediatric and adult cancers. Acute vincristine-induced
peripheral neuropathy is common (~25-40% of patients), often disrupting curative therapy, whereas chronic
neuropathy causes long-term morbidity that compromises quality of life. In part because of a paucity of
genetically diverse human models of CIPN, there are no preventive measures or effective treatments for this
devastating adverse drug effect. Our multi-disciplinary team comprising three established programs based at
the University of Chicago, St. Jude Children's Research Hospital (SJCRH), and Boston Children's
Hospital/Harvard Medical School capitalizes on novel stem cell technology to create patient-derived human
neurons, through differentiation of induced pluripotent stem cells (iPSCs) created from the blood of adult
survivors of childhood acute lymphocytic leukemia (ALL) treated with vincristine. We are taking a bedside to
bench strategy by using blood from cancer survivors with severe, persistent neuropathy and matched survivors
with no neuropathy (controls) to create an in vitro model that will allow mechanistic studies of CIPN and
provide a means to screen compounds for the prevention or treatment of CIPN. The adult survivors of
childhood cancer have extensive genetic and phenotypic information to determine extent of motor and sensory
neuropathy including nerve conduction studies to determine axonal integrity, and tests of manual dexterity,
balance and gait speed to determine physical function (all part of SJCRH-SJLIFE with existing IRB approved
protocols). We are choosing those at the extremes of the phenotypic spectrum (severe neuropathy or no
neuropathy), allowing us an unprecedented opportunity to use a combination of morphological and functional
studies to test whether the iPSC-derived neurons recapitulate the phenotypes of the individuals from which the
neurons were derived (i.e., significantly more chemotherapeutic damage to neurons from patients with severe
toxicity compared to neurons from controls following in vitro treatment with vincristine). If the phenotypes prove
to be significantly divergent, the patient-derived neurons can be used in high throughput screening to identify
drugs that reverse the effect of chemotherapeutic damage. The impact is high because, to our knowledge, this
will be the first effort to evaluate chemotherapeutic toxicity in neurons from well-phenotyped patients. Our aims
are: 1) To identify an in vitro toxicity readout in patient-derived neurons that parallels the clinical phenotype
from well-phenotyped cancer survivors following treatment as children with vincristine; 2) To determine the
effect of a SNP (rs924607) in the promoter of CEP72 on its mRNA expression and its effects on sensitivity to
vincristine in motor neurons, which our preliminary data indicate increases sensit...

## Key facts

- **NIH application ID:** 9944467
- **Project number:** 5R21CA222764-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Mary Eileen Dolan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $176,175
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944467

## Citation

> US National Institutes of Health, RePORTER application 9944467, Modeling Vincristine-Induced Severe and Persistent Neuropathy (5R21CA222764-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944467. Licensed CC0.

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