Differential methylation and expression of genes in the hypoxia-inducible factor 1 signaling pathway are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors and with preclinical models of chemotherapy-induced neuropathic pain

Abstract

Background Paclitaxel is an important chemotherapeutic agent for the treatment of breast cancer. Paclitaxel-induced peripheral neuropathy (PIPN) is a major dose-limiting toxicity that can persist into survivorship. While not all survivors develop PIPN, for those who do, it has a substantial negative impact on their functional status and quality of life. No interventions are available to treat PIPN. In our previous studies, we identified that the HIF-1 signaling pathway (H1SP) was perturbed between breast cancer survivors with and without PIPN. Preclinical studies suggest that the H1SP is involved in the development of bortezomib-induced and diabetic peripheral neuropathy, and sciatic nerve injury. The purpose of this study was to identify H1SP genes that have both differential methylation and differential gene expression between breast cancer survivors with and without PIPN. Methods A multi-staged integrated analysis was performed. In peripheral blood, methylation was assayed using microarray and gene expression was assayed using RNA-seq. Candidate genes in the H1SP having both differentially methylation and differential expression were identified between survivors who received paclitaxel and did (n = 25) and did not (n = 25) develop PIPN. Then, candidate genes were evaluated for differential methylation and differential expression in public data sets of preclinical models of PIPN and sciatic nerve injury. Results Eight candidate genes were identified as both differential methylation and differential expression in survivors. Of the eight homologs identified, one was found to be differential expression in both PIPN and “normal” mice dorsal root ganglia; three were differential methylation in sciatic nerve injury versus sham rats in both pre-frontal cortex and T-cells; and two were differential methylation in sciatic nerve injury versus sham rats in the pre-frontal cortex. Conclusions This study is the first to evaluate for methylation in cancer survivors with chronic PIPN. The findings provide evidence that the expression of H1SP genes associated with chronic PIPN in cancer survivors may be regulated by epigenetic mechanisms and suggests genes for validation as potential therapeutic targets.

Ganglioside Monosialic Acid Alleviates Peripheral Neuropathy Induced by Utidelone Plus Capecitabine in Metastatic Breast Cancer From a Phase III Clinical Trial

“…Utidelone and capecitabine may be associated with damage to dorsal root ganglion (DRG) neurons via energy failure or transport deficits, similar to oxaliplatin and taxane. Some studies suggested that oxaliplatin and taxane were associated with a dose-dependent reduction in plasma nerve growth factor (NGF), an essential mediator of the activity of DRG neurons (16)(17)(18)(19)(20)(21). GM1 was approved as a neuroprotective agent against excitotoxic agents and ischemia with the mechanism of modulating neuronal plasticity and memory formation.…”

Pharmacologic Management of Persistent Pain in Cancer Survivors

“…The impact of PNS and CNS neuroinflammatory and neuroimmune processors on CIPN are being increasingly considered [ 37 , 57 , 76 ]. Many chemotherapeutic compounds, including paclitaxel, increase the serum levels of cytokines and monocytes in patients [ 77 , 78 ] and pre-clinical CIPN models. Evidence suggests that chemotherapeutic agents alter both the innate and adaptive immune responses.…”

Multi-Staged Data-Integrated Multi-Omics Analysis for Symptom Science Research

“…Work has already begun in symptoms science research to utilize a MS-DIMO analysis. In Box 1, we present three case exemplars that used a MS-DIMO analysis and discuss how this approach strengthened the study findings (Hong et al, 2018; Kober et al, 2020; Saligan et al, 2018).…”