番茄社区

ATLANTA -- A novel analogue of ethoxyquin prevented nerve damage from the chemotherapy agent paclitaxel (Taxol) in mice, researchers reported here.

Building on previous work with ethoxyquin, an FDA-approved preservative used in pet food, the analogue EQ-6 prevented nerve fiber loss and sensory changes, and reduced protein markers of nerve damage in animal models of chemotherapy-induced peripheral neuropathy, reported Ahmet Hoke, MD, PhD, of Johns Hopkins University in Baltimore, and colleagues in a symposium presentation at the American Neurological Association (ANA) annual meeting.

"We have developed a potential treatment to prevent a major side effect of chemotherapy drugs," Hoke, who was awarded the Wolfe Neuropathy Research Prize at the ANA meeting for this work, told 番茄社区. "The parent compound came out of a phenotypic screen we did several years back. Now we have a novel analogue that has better drug-like properties."

Chemotherapy-induced neurotoxicity is significant problem in cancer therapy, said Timothy Gershon, MD, PhD, of the University of North Carolina in Chapel Hill, who was not involved with the research.

"Many patients on treatment for cancer experience chemotherapy-induced neurotoxicity, and this toxicity which can be disabling, limits the dosing of potentially effective agents," Gershon told 番茄社区. "Finding ways to reduce chemotherapy-induced neurotoxicity may allow more patients to be treated with chemotherapy, and at higher doses. The innovative research leading to the discovery of EQ-6 has the potential to move the field dramatically forward."

Paclitaxel is one of the most commonly used cancer drugs that causes peripheral neuropathy, Hoke said. Current therapies target symptomatic control and there is no effective drug for prevention.

The antidepressant duloxetine (Cymbalta) has been shown to reduce neuropathic pain associated with taxane or platinum-based chemotherapy, for example. Cryotherapy -- wearing frozen gloves and socks -- has helped prevent neuropathy in some breast cancer patients treated with paclitaxel.

Hoke and colleagues first identified in 2013, demonstrating in mouse models that ethoxyquin modulated the chaperone activity of heat shock protein 90 (Hsp90) and blocked the binding of the proteins ataxin‐2 and SF3B2. Reducing the levels of these proteins prevented the axonal degeneration that paclitaxel causes. In 2016, they showed in mouse models.

In both the paclitaxel and the cisplatin studies, Hoke's group showed ethoxyquin prevented peripheral neuropathy without blocking the chemotherapy drug's ability to kill tumor cells. To improve ethoxyquin's drug-like properties, they synthesized a novel analogue (6-(2-amino)-ethoxy-2, 2,4-trimethyl1,dihydroquinoline), naming it EQ-6.

At doses similar to the parent compound, EQ-6 prevented loss of epidermal nerve fibers in mice hind paws in two separate studies. Thermal hypoalgesia caused by paclitaxel also was prevented and sensory evoked responses were preserved. This neuroprotection was associated with a reduction in SF3B2 levels in sensory neurons, Hoke noted.

Pharmacokinetic studies showed EQ-6 had an oral bioavailability of 10%, similar to ethoxyquin, but a higher tissue concentration in brain and sciatic nerve. There was no observable toxicity in urine and blood chemistry, or liver, heart, or kidney pathology.

EQ-6 also showed efficacy in other animal models including cisplatin and diabetic neuropathy, but the researchers are focusing on paclitaxel as they prepare for investigational new drug (IND)-enabling manufacturing and safety studies. "Clinically, breast cancer patients who receive paclitaxel represent a large population," Hoke said, anticipating that, if all goes as hoped, phase I human trials of EQ-6 can start in about 18 months to 2 years.