A3AR Agonists May Help Prevent Chemotherapy-Induced Neuropathic Pain

A highly selective small molecule A3AR agonist blocked development of oxaliplatin-induced neuropathic pain without interfering with anticancer effects.

Clinicians may soon have a new tool for preventing chemotherapy-induced neuropathic pain (CINP). Writing the in the journal Pain, researchers at Saint Louis University (SLU) report that A3AR agonists, which are already in advanced clinical trials as anticancer agents, may actually work as as an adjunct to chemotherapy, to prevent CINP.

Daniela Salvemini, PhD, a professor of pharmacology and physiology at SLU in Saint Louis, said there are nearly 14 million cancer survivors in the United States and many suffer from long-term side effects of CINP. Yet, there are no proven strategies for prevention or treatment. In the current investigation, Salvemini et al studied the platinum-based chemotherapy drug oxaliplatin, commonly used to treat colorectal cancer. Oxaliplatin is often used in conjunction with with fluorouracil and folinic acid (leucovorin) in therapy for advanced cancer.

The team discovered that chemotherapy alters the signaling of a protective molecule in the spinal cord at one of its receptor subtypes (A3 adenosine receptor). “Restoring signaling with a small-molecule highly selective A3AR agonist given only during the period of oxaliplatin blocked the development of oxaliplatin-induced neuropathic pain without interfering with anticancer effects,” said Salvemini.

She noted it was remarkable that the effects were long-lasting after discontinuation of this A3AR agonist. Also remarkable was that protective effects of the A3AR compounds were mediated by a potent endogenous anti-inflammatory and neuroprotective cytokine, interleukin 10.

“Chemotherapy-induced neuropathic pain is a major dose-limiting toxicity of a widely used chemotherapeutic in different classes,” Salvemini and colleagues wrote. Studies suggest that more than 60% of patients with colorectal cancer who receive oxaliplatin develop CINP.

Salvemini said the current findings suggest that small-molecule A3AR agonists could be given as adjunct to chemotherapy to block the development of pain, potentially allowing for better anticancer dosing regimens. “Moreover, our work suggests that these novel non-narcotic analgesics could be given in settings where the cancer has been eradicated but the pain persists, thus improving the quality of life of these patients,” said Salvemini.

Furthermore, CINP is a huge unmet medical need that impacts treatment as well as quality of life. Salvemini said there are very few drugs available to manage neuropathy-related pain, and what is used currently often has limited efficacy and many side effects. Having a novel non-narcotic analgesic that could be used to prevent and treat established chemotherapy-induced pain could have a major impact on patients in treatment, in remission, and in survivors, according to Salvemini. Since A3AR agonists are currently being studied in advanced clinical trials as novel anticancer agents, they could make it to the clinic relatively soon, and may have more than one role to play.