A French-American research team discovered that the investigational compound Carba1 may prevent chemotherapy-induced peripheral neuropathy (CIPN) in preclinical models. According to a study published in Science Advances, this molecule appears to protect nerve cells from damage caused by common chemotherapeutic agents while maintaining anticancer efficacy.

A French National Centre for Scientific Research (CNRS)-led research team identified a molecule that may prevent CIPN, offering a potential therapeutic approach for a common and currently untreatable complication of cancer treatment.

CIPN affects 70%-80% of patients receiving chemotherapy, causing persistent tingling, burning sensations, pain, and numbness in the hands and feet that can persist long after treatment ends.

Speaking with Medscape’s French edition, Laurence Lafanechère, PhD, CNRS Research Director at the Institute for Advanced Biosciences, Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309 in Grenoble, France, and co-author of the study, said, “The neuropathies we studied are induced by chemotherapy. While these treatments don’t significantly penetrate the brain, they damage peripheral nerves in most patients to varying degrees — from mild tingling to severe pain and balance disturbances.”

Clinical Need

“Approximately 25% of patients experience persistent symptoms long after chemotherapy is stopped. I received testimonies from patients who could no longer write or sew because of it. Currently, there are no preventive or curative treatments available. Sometimes, the pain is so debilitating that doctors are forced to reduce the chemotherapy dose. Patients are relieved with painkillers or anti-epileptics, but it’s like putting a plaster on a wound.”

She added, “Doctors sometimes have patients wear cooling gloves or booties to constrict microvessels and reduce exposure of extremities to chemotherapy. However, some studies indicate that this is effective, whereas others indicate that it is not. Furthermore, it’s not very pleasant for patients.”

Research Discovery

Lafanechère stated, “These small tubes are found in cells and serve to make cables that pull and separate chromosomes during cell division. Therefore, they are targeted by chemotherapy, particularly those on the basis of taxane.

However, they are also a type of “rails” for axons in nerve cells. Microtubules are responsible for axonal transport, and this is why paclitaxel is neurotoxic.”

“I knew that Taxol (paclitaxel) was extremely toxic, and I wanted to find a molecule that would boost its effectiveness while reducing the doses,” said Lafanechère.

After testing 8000 compounds from the Center for Drug Studies and Research in Normandy, France, the team identified Carba1, a molecule belonging to the carbazole family.

“I looked for those that are non-toxic but which, in combination with this very low dose of paclitaxel, could have a toxic effect on cancer cells,” she said. Published 5 years ago, these results led to the discovery of Carba1.

Neuroprotection

“I tried to understand its mechanism of action, but at the time I was rather disappointed because it didn’t have many possible applications, apart from lowering the doses of paclitaxel,” Lafanechère said.

“It targeted the same thing, tubulin, and facilitated the binding of paclitaxel. I showed that Carba1 could synergize with paclitaxel in cells and in animal models, but I was afraid of finding the same side effects.”

However, a review of the literature revealed that the carbazole nucleus has previously been described as having an effect on neuropathies.

“I got in touch with an American researcher working on this subject,” said Francesca Bartolini, PhD, professor of pathology and cell biology in the Department of Pathology and Cell Biology at Columbia University Irving Medical Center in New York City.

“I sent her the molecule, and she evaluated it,” Lafanechère recalled. “Very enthusiastic, she called me back saying I had found the holy grail! Carba1 not only reduced the doses of paclitaxel but also protected neurons.”

Under fluorescence microscopy, damaged neurones, which normally appear as a string of pearls rather than as smooth fibres, remained intact after treatment. “When we put them in contact with Carba1 and paclitaxel, they remained smooth. We were very happy with these results,” she added.

The researchers then evaluated Carba1 with other chemotherapies, including cisplatin (a cytostatic antineoplastic) and bortezomib (a proteasome inhibitor), and found that the protective effect was maintained.

Molecular Mechanism

Researchers have investigated Carba1’s mechanism by comparing control and treated cells. “More specifically, our molecule increased the production of NAD, an important cofactor in all cellular energy mechanisms, which typically declines when neurons degenerate,” said Lafanechère.

Researchers have discovered that Carba1 activates the enzyme nicotinamide phosphoribosyltransferase, preventing energy depletion, which leads to cell death.

“We validated these results using three different models: cultured neurones, dorsal root ganglion explants, and animal behavioural models. Each demonstrated this neuroprotective effect,” she reported.

In animal studies, pain levels remained at baseline when Carba1 was administered before and alongside paclitaxel. Crucially, the research showed Carba1’s effect was not merely analgesic.

“We counted the nerve endings in the animals’ paws and found the same number as the controls, showing that our molecule was not just a painkiller,” said Lafanechère. “We also measured the serum neurofilament light chain (NfL), a biomarker released into the blood during neuronal degeneration. All three markers showed levels comparable to controls, confirming protective effect of Carba1.”

After presenting these results at the Peripheral Nerve Society Congress in the UK, the research team filed two patents: “Two patents have been filed, one for protection against neuropathies and the other for synergy with paclitaxel,” she said.

Start-Up to Advance Development

The initial funding for the start-up was secured through the Pré-Maturation Innovation Program from CNRS, with subsequent support from Linksium, the Science and Technology Transfer Office in Grenoble, France.

Lafanechère enlisted partners including co-author Lauriane Bosc, PhD, from the Institute for Advanced Biosciences, alongside fundraising and business development specialists Philippe Bordeau and Victor Juarez Perez, who are affiliated with the start-up Saxol in Grenoble, France. “They bring essential drug development experience that complements my research focus,” Lafanechère noted.

The researchers’ primary objective was to secure further investment to advance the project. “We aim to raise funds to continue development — focusing on formulation, dosage, and safety studies — with a target of 5-7 years before potential partnership with a larger pharmaceutical company capable of conducting clinical trials,” Lafanechère said.

Lafanechère believes that this molecule holds promise for treating other forms of neuropathy, including those associated with diabetes, aging, and amyotrophic lateral sclerosis (also known as Lou Gehrig disease). She concluded, “For now, however, we are concentrating specifically on chemotherapy-induced neuropathies — there is more than enough work to be done in this area alone.”

This story was translated from Medscape’s French edition.