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< BACK TO CLINICAL BREAKTHROUGHS IN ONCOLOGY

Medecine on Table

ONCOLOGY

CANCER DRUG MAY HAVE POTENTIAL FOR PAIN RELIEF

Featuring:  Paul DeCaen, PhD
​​
​​Scientists have discovered a previously unknown receptor site in a voltage-gated sodium channel, according to a study published in Molecular Cell.
​
Sodium channel inhibitors have been investigated as a promising delivery route for non-opioid pain drugs, but new drug development is a time- and resource-intensive process. According to Paul DeCaen, PhD, assistant professor of Pharmacology and a co-author of the study, however, this receptor can be targeted with analogues of Tamoxifen — a drug currently approved to treat breast cancer — presenting a worthwhile opportunity.

“Despite the clear need, the time and cost of developing new analgesics is escalating. Currently, bringing a new drug to market costs more than three billion dollars and requires at least ten years,” DeCaen said. “Maybe we can bypass the time and cost of drug development by repurposing Tamoxifen analogues for the treatment of chronic and neuropathic pain.”

Peripheral nerve sodium channels are an important element of neuropathic pain signaling pathways in nerve and cardiac cells. While harmful genetic mutations in these pathways can cause epilepsy and cardiomyopathy, recent efforts to develop non-opioid pain relief drugs have highlighted the potential of modulating these pathways for pain management.

“This is primarily because sodium channel inhibitors are highly effective analgesics and are not associated with addiction— a dangerous side effect associated with prescribed opioids,” DeCaen said.

Tamoxifen is a 40-year-old drug commonly prescribed to treat breast cancer, binding to estrogen that the cancer would otherwise use to grow. Some side effects and safety limitations have been linked to off-target effects in sodium channels, but those specific mechanisms have remained largely unexplored, according to DeCaen.

In the current study, scientists examined Tamoxifen’s binding sites in the NavMs voltage-gated sodium channel, finding two previously unknown sites near the gate of the channel. While these may explain some of Tamoxifen’s side effects, DeCaen and his collaborators were more interested in their potential to generate pain relief.

Using a Tamoxifen analogue that had no effect on the estrogen receptor — to avoid interfering with estrogen’s role in pain management — they found the analogue helped inhibit the sodium channel pain pathway.

“It was highly effective at blocking sodium channels and silencing overactive sensory neurons which transmit pain signals to the brain,” DeCaen said.

The broad impact of the opioid crisis underscores the need for effective non-opioid pain medication, according to DeCaen. Repurposing Tamoxifen analogues for this new function could be a more time- and cost-effective way to bring non-opioid pain relief to patients.

“Tamoxifen’s drug safety, metabolism and distribution is well characterized by several decades of use as treatment for breast cancer,” DeCaen said. “Thus, the short and long-term potential drug toxicity, pharmacokinetics and pharmacodynamics associated orally-dosed Tamoxifen is already established within a large, heterogenic human population.”
This study was supported by grants 1R56DK119709-01, 4R00DK106655, 1R01 DK123463-01 and P30 DK090728from the National Institute of Diabetes and Digestive and Kidney Diseases; NU GoKidney George M. O’Brien Kidney Research Core Center grant P30 DK11485; and the American Society of Nephrology.

This article was originally published in the Feinberg School of Medicine News Center on March 3, 2021.
Paul DeCaen, PhD Headshot
Paul DeCaen, PhD, assistant professor of Pharmacology, was a co-author of the study published in Molecular Cell.

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