A groundbreaking study has uncovered a shared mechanism that links oral cancer pain and opioid tolerance, offering a potential new treatment strategy for both conditions. The research, published in Science Signaling, reveals that Epidermal Growth Factor Receptor (EGFR) signaling in the tissue surrounding oral cancers increases nerve sensitivity while also reducing the effectiveness of opioids. This discovery paves the way for a novel approach to managing oral cancer pain and preventing or reversing opioid tolerance.
The study's lead researcher, Yi Ye, PhD, from NYU College of Dentistry, suggests that repurposing existing cancer drugs that block EGFR could be a promising strategy. Ye explains, 'By blocking EGFR, we may be able to manage oral cancer pain and potentially prevent or reverse opioid tolerance, offering a new treatment avenue for patients.'
Oral cancer pain is notoriously challenging to manage, often requiring high doses of opioids that can lead to tolerance and addiction. Despite the risks, opioids are still considered the gold standard for treating oral cancer pain. However, the study highlights a shared molecular driver behind both cancer and pain, suggesting that targeting this mechanism could provide a more effective and safer approach.
The research team, including scientists from NYU Dentistry, The University of Texas MD Anderson Cancer Center, and Loma Linda University School of Dentistry, studied human tissue samples and mice with oral cancer. They discovered that cancer cells and nearby glial cells secreted EGFR ligands, which activated the EGFR receptors on nerves associated with oral cancer tumors. This activation led to the hyperactivity of the glutamate N-methyl-d-aspartate receptor (NMDAR), a key player in pain signaling and opioid tolerance.
In further experiments, the researchers found that EGFR ligands increased pain and reduced morphine's effectiveness. Conversely, administering EGFR inhibitors reduced pain and restored morphine's analgesic properties. This finding is clinically significant, as it reveals a link between EGFR signaling and NMDAR hyperactivity, a mechanism that intensifies pain signaling and diminishes opioid effectiveness.
The study's authors propose a novel approach to treating oral cancer pain: repurposing EGFR inhibitors already approved for cancer treatment. These drugs have been extensively studied, and their safety profiles are known. By targeting EGFR, the approach aims to reduce pain and opioid reliance while simultaneously controlling cancer. Moran Amit, MD, PhD, emphasizes the potential of this strategy, stating, 'This study provides a rationale for repurposing EGFR inhibitors, offering a dual benefit of cancer control and pain management through a non-opioid, biologically rational approach.'
The research team is now analyzing patient data, including tumor and blood samples, self-reported pain scores, and opioid use, to further explore the role of EGFR and its ligands in oral cancer pain and opioid tolerance. They are also leveraging an existing clinical trial to evaluate the impact of EGFR inhibitors on pain relief.
The study's findings hold promise for revolutionizing cancer pain management, offering a targeted approach that mitigates the adverse effects of opioids. As Ye concludes, 'If our mechanism holds true, repurposing EGFR inhibitors could lead to rapid translation and provide quick relief for patients. This new treatment approach offers hope to both patients and clinicians treating oral cancer.' The research team includes Naijiang Liu, Xiaojie Shi, Maria Daniela Santi, Maria Fernanda Pessano Fialho, Rocco Latorre, Nigel Bunnett, Shao-Rui Chen, Hong Chen, Tongxin Xie, Frederico Gleber-Netto, and Dong Minh Phuong.
