Photo Credit: iStock.com/jmimages

The oncogene AEG-1 shows promise as a target for managing chemotherapy-induced peripheral neuropathy, according to a recently published study.

The oncogene astrocyte elevated gene-1 (AEG-1) shows promise as a target for managing chemotherapy-induced peripheral neuropathy (CIPN), a common, painful, dose-limiting side effect of chemotherapy treatment, according to a recent study published in Brain, Behavior and Immunity.

“Currently, there are no FDA-approved medications designed to specifically treat or prevent CIPN in cancer patients, and the current clinical approach for the management of it is inadequate,” said study author M. Imad Damaj, PhD, VCU Massey Comprehensive Cancer Center, in a press release. “Our findings could help pave the way for the development of an entirely new and effective therapeutic option for CIPN.”

The Role of AEG-1 in CIPN Development

The research team’s findings suggest that AEG-1 actively regulates the inflammation responsible for the nerve damage seen in CIPN. Although AEG-1 has been previously linked to inflammation and tumor growth, this is the first research to explore its role in the development of CIPN.

Chemotherapy drugs are commonly linked to the development of CIPN. Although many patients recover within a few months, approximately 25%-30% experience chronic neuropathy. For some, the pain is severe enough to force a change in chemotherapy drugs, often to less effective alternatives. To manage the pain, patients are sometimes prescribed opioids, which carry a risk of addiction.

Study co-author Devanand Sarkar, PhD, MBBS, emphasized the potential for new treatments that avoid the reliance on addictive pain medications. “We’ve identified a promising strategy through which we can pursue new targeted treatments as an alternative,” he explained.

Investigating AEG-1 in Animal Models

The research team investigated whether AEG-1 contributes to the development and maintenance of CIPN pathologies by using global (AEG-1 KO) and myelocyte-specific knockout (AEG-1ΔMAC) strains in an animal model of CIPN that replicates specific human clinical phenotypes.

“We hypothesized that inhibition of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the development and maintenance of CIPN,” the study authors wrote.

Key Findings: AEG-1 Deletion Prevents CIPN Pathologies

The results showed that global AEG-1 deletion prevented the development of CIPN pathologies caused by paclitaxel (Taxol) (PAC) and oxaliplatin. PAC treatment increased AEG-1 and proinflammatory cytokine/chemokine expression in the Dorsal root ganglions (DRGs) of wild-type mice and peritoneal macrophages isolated from C57BL/6J mice.

“However, in the absence of AEG-1 expression, PAC-induced neuroinflammation was completely halted in the DRGs of AEG-1 KO mice,” the authors wrote.

This effect was also observed in AEG-1ΔMAC mice, which had reduced NF-κB protein levels and fewer F4/80+ macrophages in the lumbar DRGs after PAC treatment. The authors suggested that targeting AEG-1 in macrophages could not only help prevent CIPN but also reduce tumor size.

Future Research

The next step for the research team is to evaluate the effectiveness of targeting AEG-1 in clinical trials, to develop therapies that can prevent or even reverse the effects of CIPN in patients.

“If effective, this double weapon approach may represent a holistic therapeutic strategy that can be utilized to prevent both cancer progression and chemotoxicity, which could drastically improve survivorship and quality of life for patients diagnosed with cancer,” Dr. Damaj said.