Splicing kinase inhibition as adjunct therapy for chemotherapy-induced peripheral neuropathy and pain.

The research will investigate the prevention and treatment of the late side effects of chemotherapy on the sensory nervous system. The chemotherapy agent vincristine, which is commonly used to treat cancers in children and young people, has direct effects on the sensory nerves. This is because vincristine affects nerves with the longest fibres/axons such as those that innervate the most distant parts of the body, the hands and feet. We found that vincristine causes both immediate and direct effects on these nerves that result in pain, and that pain does not occur solely as a result of nerve damge but because of these direct actions. Vincristine does also cause longer term nerve damage of course, which would lead to longer term pain as this is often not repaired on cessation of chemotherapy. These effects contribute to both the dose-limiting side effects (immediate pain) during treatment and to the long-lasting treatment-related neuropathic pain that affects an increasing number of cancer survivors. We hypothesise that this damage to neurons occurs through changes in pre-mRNA alternative splicing, as a result of vincristine treatment. The project will test the effect of novel inhibitors of alternative splicing on pain and neuronal damage in sensory neurons in vivo and in vitro, and will also incorporate testing of compounds on relevant tumour cells, so ensure that any potential adjunct therapy does not affect cancer treatment.