# (PQ9)Mechanistic Role of APE1 and BER in chemotherapy-induced peripheral neuropathy

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $537,592

## Abstract

PROJECT SUMMARY / ABSTRACT
As cancer treatments continue to become more effective with increases in patient survival, we are recognizing
clinical consequences of therapy that negatively impact the course of therapy and the quality of life of patients
and survivors. Of major clinical significance is chemotherapy-induced peripheral neuropathy (CIPN), which can
be severe enough to necessitate reducing or stopping treatment and thus can compromise therapy.
Furthermore, CIPN can continue long after therapy is stopped and is irreversible in a significant number of
patients. Compounding this problem is a lack of effective treatments available to prevent or reverse CIPN. The
lack of effective prevention or treatment for CIPN is a direct consequence of not understanding the
mechanisms that cause the neurotoxicity. As such, examining the provocative question of “What are the
molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe
adverse sequelae?” will be addressed in our studies using animal models and an array of endpoints measuring
changes in sensory neuronal function which parallel clinical symptoms of CIPN. Most CIPN develops over time
with few if any acute symptoms after initial therapy, but increases in severity with continued therapy. The delay
in onset of neuropathy suggests that there is an aggregate effect of drugs over time that results in a long-term
alteration in neuronal function. Consequently, it is important to examine the mechanisms by which cumulative
exposure to chemotherapeutics might result in neurotoxicity. Previously, we demonstrated that reducing the
activity of the DNA base excision repair (BER) pathway by reducing expression of the apurinic/apyrimidinic
endonuclease/redox factor (APE1/Ref-1 or APE1) exacerbated neurotoxicity produced by anticancer treatment,
whereas augmenting the repair activity of APE1 attenuated the neurotoxicity. These data support the notion that
DNA damage is a critical mechanism by which the function of sensory neurons is altered by chemotherapeutics.
Indeed, it is likely that in post-mitotic cells (e.g. neurons) DNA damage could result in abnormal protein production
that is maintained unless the DNA damage is repaired, reversing the aberrant transcriptional effects of the
neurotoxins. Therefore, we hypothesize that APE1 is a critical protein for protecting neurons from cancer
therapies and that augmenting APE1 DNA repair activity will prevent and reverse chemotherapy-induced
alterations in sensory neuronal function. Furthermore, fully understanding the DNA damage and the
mechanisms by which the BER pathway reverses this damage will lead to the identification of novel
targets for CIPN prevention or therapy. To address these hypotheses, we propose three aims which will
determine whether augmenting APE1 repair activity in vivo prevents or reverses DNA damage in sensory
neurons and the subsequent alterations in sensory neuronal function caused by anticancer drug ad...

## Key facts

- **NIH application ID:** 9901467
- **Project number:** 5R01CA205166-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** JILL C FEHRENBACHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,592
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901467

## Citation

> US National Institutes of Health, RePORTER application 9901467, (PQ9)Mechanistic Role of APE1 and BER in chemotherapy-induced peripheral neuropathy (5R01CA205166-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901467. Licensed CC0.

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