# Genetic basis of chemotherapy-induced neuropathy in a reduced complexity cross

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $446,100

## Abstract

Paclitaxel is a cytoskeletal drug commonly used for the treatment of breast, lung, and
ovarian cancer. Peripheral neuropathic pain (CIPN) is one of the most common and
serious adverse effects experienced by cancer patients treated with paclitaxel. CIPN can
be a dose-limiting factor for chemotherapy, leading to premature termination of
treatment, thereby influencing survival and quality of life. Currently, no therapies have
been identified that address the underlying pathogenic mechanisms such as
neurodegeneration; in fact, the current symptomatic therapies are frequently ineffective
in mitigating the painful symptoms of CIPN in the majority of patients. Therefore, the
identification of alternative forms of therapy is a crucial medical need. The primary
objective of this proposal is to identify novel genetic factors that contribute to paclitaxel-
induced neuropathy in mice. We observed pronounced paclitaxel-induced CIPN in
C57BL/6NJ strain but not in the closely related C57BL/6J substrain. Because the
parental substrains are nearly genetically identical, quantitative trait locus (QTL)
mapping in an experimental F2 cross (Reduced Complexity Cross; RCC) will greatly
facilitate the identification of novel genetic factors that underlie differences in CIPN
behaviors. In Aim 1, we will use the RCC to map genomic regions, or QTLs, that are
causally associated with susceptibility versus resilience to multiple measures of CIPN.
In Aim 2, we will conduct transcriptome analysis via mRNA sequencing (RNA-seq) of
spinal and peripheral neuronal regions in control mice and paclitaxel-treated mice from
the parental male and female C57BL/6J and C57BL/6NJ substrains. The transcriptome
in control mice will aid in identifying differentially expressed, candidate CIPN
susceptibility genes underlying the QTLs . Genes that are differentially expressed as a
consequence of paclitaxel will reveal changes in the transcriptome relevant to central
and peripheral neuronal plasticity and the behaviors/changes that support the long-term
establishment of CIPN that may be important for treatment reversal. In Aim 3, we will
validate candidate quantitative trait genes and functional variants that influence
susceptibility to and establishment of CIPN. These studies will provide rapid genetic and
neurobiological insight into CIPN. Future studies will test for translational potential in
human genetics, human experimental model systems (e.g., hIPSCs), and new potential
therapeutics to combat the debilitating side effects of CIPN in cancer patients.

## Key facts

- **NIH application ID:** 9851833
- **Project number:** 5R01CA221260-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** CAMRON D BRYANT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,100
- **Award type:** 5
- **Project period:** 2018-02-07 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851833

## Citation

> US National Institutes of Health, RePORTER application 9851833, Genetic basis of chemotherapy-induced neuropathy in a reduced complexity cross (5R01CA221260-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851833. Licensed CC0.

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