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 administration as well as determining the mechanisms mediating APE1-induced neuroprotection of isolated sensory neurons.

Public Health Relevance

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent dose-limiting toxicities of anti-cancer therapy which can be debilitating and in some patients irreversible. To date, there are no FDA- approved treatments to prevent or reverse CIPN, which highlights the need for research to understand the mechanisms mediating this toxicity to develop novel therapies. Our studies will focus on APE1 and DNA base excision repair as a critical protein/pathway for protecting neurons from cancer therapies such that augmenting APE1 DNA repair activity will prevent and reverse chemotherapy-induced alterations in sensory neuronal function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA205166-01A1
Application #
9305492
Study Section
Special Emphasis Panel (ZCA1-SRB-1 (J1))
Program Officer
Alley, Michael C
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$536,312
Indirect Cost
$194,984
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Sardar Pasha, Sheik Pran Babu; Sishtla, Kamakshi; Sulaiman, Rania S et al. (2018) Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization. J Pharmacol Exp Ther 367:108-118
Kelley, Mark R; Fehrenbacher, Jill C (2017) Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage. Neural Regen Res 12:72-74
Ding, Jixin; Fishel, Melissa L; Reed, April M et al. (2017) Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia. Mol Cancer Ther 16:1401-1411
Fehrenbacher, Jill C; Guo, Chunlu; Kelley, Mark R et al. (2017) DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1. Neuroscience 366:23-35
Darby, Lisa M; Meng, Hongdi; Fehrenbacher, Jill C (2017) Paclitaxel inhibits the activity and membrane localization of PKC? and PKC?I/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons. Mol Cell Neurosci 82:105-117
Shah, Fenil; Logsdon, Derek; Messmann, Richard A et al. (2017) Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol 1:
Shah, Fenil; Goossens, Emery; Atallah, Nadia M et al. (2017) APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma - characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing. Mol Oncol 11:1711-1732