Tingling in the hands and feet, burning sensations, pain, loss of sensation, numbness… Peripheral neuropathy is one of the most common side effects of chemotherapy, affecting up to 90% of patients with certain treatments. Its severity sometimes leads healthcare providers to adjust or even reduce chemotherapy doses, which can diminish the treatment’s effectiveness.

In one out of every four cases, these nerve damage symptoms persist for months or even years after treatment ends. They serve as a daily reminder to patients that they had cancer—even after their hair has grown back and the nausea or fatigue has subsided. No right to be forgotten, even after the disease has been defeated

To date, aside from wearing gloves and cooling socks during chemotherapy sessions—a method that is not always effective and is often unpleasant—no preventive treatment exists. A few palliative medications are used to alleviate pain, with limited effectiveness.

Our team, in collaboration with researchers from the United States and France, has just achieved a major breakthrough with the discovery of a compound, named Carba1, that can protect neurons from the toxic effects of chemotherapy while enhancing the effectiveness of certain cancer treatments. This research has just been published in the journal *Science Advances*.

One molecule, two targets

Carba1 belongs to the carbazole family, a class of molecules developed by researchers at the Normandy Center for Drug Studies and Research (CERMN), with whom we have been collaborating for more than ten years.

Our research has shown that Carba1 acts on two main targets.

First, Carba1 interacts with tubulin, the building block of microtubules. Depending on the cell’s needs, these building blocks can assemble to form either “cables” capable of pulling and separating chromosomes during cell division, or “rails” along which molecular motors travel, transporting nutrients and organelles such as mitochondria, thereby ensuring the distribution of energy and resources throughout the cell.

This transport system is particularly essential in nerve cells, whose extensions can reach more than one meter in length—for example, the neurons that originate in the spinal ganglion, near the spinal cord, and innervate the skin of the feet. Many anticancer drugs, such as paclitaxel (Taxol) or docetaxel (Taxotere), already target these structures to block the proliferation of tumor cells. However, this action is not without consequences: neurons, which also depend on microtubules to transport their components, are affected, which is one of the major causes of neuropathies.

We have shown that Carba1 subtly modifies microtubules: it disrupts their ends, promoting the binding of paclitaxel. This interaction makes it possible to use lower doses of the anticancer drug without losing its effectiveness against tumors.

But that's not all.

More Resilient Neurons

Second, upon closer examination of Carba1’s properties, we discovered that it also acts on another front: energy metabolism. Neurons are among the most energy-demanding cells, and bioenergetic failure is considered one of the main factors contributing to neuronal degeneration.

Our results show that Carba1 directly activates a key enzyme, nicotinamide phosphoribosyltransferase (NAMPT), which boosts the production of NAD⁺, a molecule crucial for energy production. As a result, neurons become more resistant to metabolic stress and are better able to survive the effects of chemotherapy drugs.

We confirmed the neuroprotective effect of Carba1 on neuron cultures exposed to three chemotherapeutic agents known to induce neuropathy through different mechanisms: paclitaxel (which targets microtubules), cisplatin (an alkylating agent), and bortezomib (a proteasome inhibitor).

Unlike control cultures, in which smooth and vigorous neuritic processes extend, in cultures treated with these drugs, the processes appear fragmented—a characteristic of a degenerative process. However, when neurons are exposed to these same treatments in the presence of Carba1, their extensions remain intact, indistinguishable from those in untreated cultures. These observations indicate that Carba1 effectively protects neurons from degeneration induced by these neurotoxic agents.

Encouraging results in animal studies

To take this a step further, we tested Carba1 in a rat model of neuropathy induced by paclitaxel, developed by Dr. David Balayssac in Clermont-Ferrand (Neurodol unit). This treatment causes skin hypersensitivity: the rats react to very light pressure on their paws, a sign of neuropathic pain. Histological analysis also shows a decrease in intraepidermal nerve endings, while blood samples exhibit elevated levels of NfL (neurofilament light chain), a marker of neuronal degeneration.

When Carba1 is administered before and during treatment, these changes disappear: the nerves remain intact, NfL levels remain normal, and the animals’ skin sensitivity remains unchanged. In other words, Carba1 protects neurons from paclitaxel-induced degeneration. Reassuringly, Carba1 does not affect tumor growth.

Like neurons, cancer cells consume a great deal of energy. It was therefore essential to verify that Carba1 did not have a pro-tumor effect and that it did not reduce the efficacy of paclitaxel. To determine this, we administered Carba1 alone, or in combination with a therapeutic dose of paclitaxel, to mice with transplanted tumors. The results are clear: Carba1 caused no toxic effects, did not impair the animals’ overall health, and did not stimulate tumor growth. Nor does it interfere with the anticancer action of paclitaxel.

A New Path Toward Better-Tolerated Treatments

This discovery is particularly exciting because it combines two effects that are rarely found together:

• enhance the effectiveness of anticancer drugs in the paclitaxel family (taxanes) by allowing for a reduction in dosage;

• to preserve nerve function and improve patients' quality of life during and after treatment.

Before considering a clinical trial in humans, several steps are still essential. First, the safety of Carba1 must be confirmed in animals, and the minimum effective dose and maximum tolerated dose must be determined. Finally, it will be necessary to develop a formulation suitable for administration in humans.

This mission now falls to the startup Saxol, which grew out of this research and of which I am one of the co-founders. If these steps—which are expected to take at least five years, depending on technical challenges and fundraising efforts—proceed as planned, Carba1 could become the first preventive treatment for chemotherapy-induced neuropathy—a major breakthrough that could transform the way patients experience their cancer treatment.

Carba1 represents an innovation at the intersection of chemistry, neurobiology, and oncology. By combining neuronal protection with enhanced therapeutic efficacy, this small molecule could, in the long term, reconcile cancer treatment with quality of life. For the millions of patients facing the dual challenges of cancer and neuropathic pain, it offers concrete and promising hope.