Botulinum toxin injections for the treatment of gastrointestinal cancer and obesity

Today, the problem of cancer, including cancer of the gastrointestinal tract, is extremely acute. In this regard, specialists are constantly looking for new approaches to cancer treatment. One such approach was presented by Dr. Duan Chen from the Department of Cancer and Molecular Medicine at the Norwegian University of Life Sciences and Technology (NTNU), Trondheim.

Botulinum toxin effect on the vagus nerve

Nervus vagus is called the vagus nerve because of the large number of areas of the body it innervates, as well as the various functions it performs. Nervus vagus consists of two main components: efferent and afferent fibers. Efferent fibers are associated with the autonomic nervous system and extend from the brainstem to organs such as the lungs, heart, and intestines. Afferent fibers carry sensory information from the organs back to the brainstem. Acetylcholine, which used to be called the substance of the vagus nerve, is now known as a neurotransmitter found in all autonomic ganglia (vegetative nodes), autonomously innervated organs, in neuromuscular and other synapses.

Re-prescribing is an approach to find new therapeutic indications for already approved drugs based on the mechanism of action. This approach enabled us to test botulinum toxin A and vagotomy for treatment of gastrointestinal cancer and VBLOC therapy in the treatment of obesity.

Gastrointestinal cancer treatment with botulinum toxin injections

Doctors were interested in whether the vagus nerve contributes to the development of gastrointestinal cancer, given that the muscarinic acetylcholine  M₃R receptor contributes to the proliferative effect on the gastric epithelium. In fact, most gastrointestinal cancers arise from an area of ​​lesser curvature of the stomach that contains more prominent vagus nerve endings. Therefore, doctors considered the potential role of the vagus nerve in gastrointestinal tumorigenesis.

Using various mouse models of gastrointestinal cancer, including a genetically driven, chemically driven cancer mouse model, and a Helicobacter pylori-infected mouse model, we found that vagotomy attenuated tumor cell proliferation.

Unilateral vagotomy or local injection of botulinum toxin into the stomach wall simply halted the precancerous growth, consistent with the above finding. Vagotomy, Botox injection, or systemic treatment with darifenacin (an M₃R antagonist) in later stages of gastric oncogenesis also suppressed tumor growth and enhanced the antitumor effect of chemotherapy, thereby improving survival. This antitumor effect was mediated mainly by the suppression of WNT signals that control stem cells with Lgr5 receptors through the activation of M₃R. In patients with gastrointestinal cancer, WNT signals were associated with neutral pathways, and neuronal density correlated with more severe tumors. Thus, we assumed that the nerves – it is an important part of stem cell niches and the tumor microenvironment. This suggests the potential benefit of anti-neurogenic therapies such as topical botulinum toxin injections.

Because topical injections of botulinum toxin have been successfully tested in animal models of gastrointestinal cancer, a second stage human clinical trial has been conducted at St Olave's Hospital in Trondheim. The trials used botulinum toxin injections using conventional upper GI endoscopy (https://clinicaltrials.gov/ct2/show/NCT01822210). The results of topical injections of botulinum toxin for the treatment of other types of ECT cancer are not yet known, but they are promising because botulinum toxin blocks the transmission of information between nerve and cancer cells by acting on proteins with soluble N-ethylmaleimide-responsive protein attachment factors (SNARE) . In patients with adenocarcinoma of the esophagogastric junction,

Obesity treatment with botulinum toxin injections

The role of the nervus vagus (vagus nerve) in the physiological control of food intake and body weight has been studied over the past years. It is believed that food interacts with the intestines so that the brain, through the afferent fibers of the vagus nerve, receives information about food intake, the amount of food absorbed and energy. The brain determines the rate of absorption of nutrients, their distribution, storage and mobilization through the efferent fibers of the vagus nerve, as well as the sympathetic nervous system and hormonal mechanisms. This axis leading from the gut to the brain and back is considered to be an autonomous neurohormonal pathway for the regulation of energy homeostasis.

Truncular vagotomy has been tried in the past to treat severe obesity, but without much success. Recently, an electronic device has been developed under the aforementioned name VBLOC, which blocks the subphrenic stem vagus nerve using high-frequency, low-power electrical signals. Such a device is implanted by laparoscopy and was recently approved by the FDA for the treatment of obesity in adults. The essence of the treatment is to influence the path of the vagus nerve in the axis leading from the intestines to the brain and back, to control the feeling of hunger.

For information about the study of this obesity treatment at St Olave's Hospital in Trondheim, please visit: https://clinicaltrials.gov/ct2/show/NCT02035397.

Adapted from Gastroenterologen.