Blocking chemotherapy-induced peripheral neuropathy by preserving axons

Axons are long 'wires' that conduct electrical signals from one nerve cell (neuron) to another, or convey signals from sense organs or to muscles. Their extreme length (up to one meter) makes them vulnerable to many stresses, including inherited disorders, toxins, inflammation, viruses and physical injury. This results in disorders such as multiple sclerosis, diabetic neuropathy, motor neuron disease and glaucoma. Significant progress has been made in mice in understanding how axon degeneration can be prevented, or at least delayed, in response to many of these stresses and our group has played a prominent role in this work. However, until now it has not been clear how this could be translated for application in patients.

One of the problems is that many of the stresses axons face are chronic and/or unpredictable. Long-term protection of axons, or protection at an unforeseen time, will always be more challenging that protecting them for a few days or weeks at a known time. One important disorder that fits this latter pattern is chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a dose-limiting side effect of many cancer drugs, causing intense pain. Most recipients of these cancer treatments suffer from it and around half of survivors continue to suffer afterwards, many for the rest of their lives. Recurrent stabbing, burning or tingling sensations, or numbness, particularly in hands and feet, regularly disrupt sleep and greatly reduce quality of life. Importantly, despite the long-term nature of the problem it stems from a very short and predictable treatment regime that causes axon degeneration. CIPN is an excellent candidate for preventative therapy.

This project has three parts. First, we will build on encouraging data from mouse and cell culture studies indicating that a protein we have studied for many years protects axons in CIPN models. We will extend the previous studies by testing whether it preserves axons from damage by a wider range of chemotherapy drugs, whether it protects them indefinitely and whether it reduces the pain in addition to blocking axon degeneration. Second, we recently identified a drug that preserves axons by mimicking an effect of the protective gene, so we will test whether this drug preserves axons and prevents symptoms in CIPN animal models. Importantly, this drug is already in use in man (in clinical trials for cancer in fact) so if successful here, tests to determine whether it preserves axons in man could proceed quickly. Third, we aim to find out more about the mechanism that underlies the axon degeneration leading to CIPN. In particular, we focus on the transport of essential proteins and organelles along nerves, termed axonal transport, a process known to be disrupted by some cancer drugs. We will ask whether this is common to several drugs that induce CIPN, in what way is the transport disrupted, and what are the immediate consequences that lead to axon degeneration, an area in which our expertise in this field should ensure good progress. This will help us to develop further strategies to preserve axons in CIPN.

Success in this project would be important for preventing the neurological complications that can result from cancer therapy. However, it should also be important in indicating how we might tackle other major axonal disorders. Diabetic neuropathy, which shares many symptoms with CIPN and affects over 1 million people in the UK, would be one excellent example. Multiple sclerosis, in which axons also come under temporary stress during inflammatory relapses, would be another. Until now there are no preventative therapies for any axonal disorders. By focusing on a disorder with a relatively straightforward mechanism, good animal models, and a very realistic likelihood of developing a therapy, it should be possible to make significant progress that provides important leads also for other important axonal diseases.

Axon degeneration plays a prominent, early role in many neurodegenerative conditions. Despite substantial progress in preserving axons in mice, translation remains a key challenge. This project focuses on chemotherapy-induced peripheral neuropathy (CIPN) as a particularly tractable and important disorder, and has wider implications for other peripheral neuropathies such as diabetic neuropathy, and for other disorders with axonal transport disruption such as multiple sclerosis and glaucoma.

CIPN is a neuropathic pain disorder experienced by 50-90% of cancer chemotherapy patients and a dose-limiting side effect. It is caused by axon loss during a treatment period lasting only days or weeks, but becomes a lifelong condition for around half of survivors. Quality of life is greatly reduced by chronic pain, burning, tingling and sleep disturbance and current therapies are palliative and inadequate. A prophylactic treatment is urgently needed to protect axons and thereby prevent or minimise CIPN.

The underlying mechanism in CIPN is believed to involve axonal transport impairment. Other mechanisms have been proposed but this model fits with the ability of the slow Wallerian degeneration protein (WldS) to preserve axons in two CIPN models. However, important questions remain. We have made significant advances in understanding why axons degenerate when axonal transport is impaired. We have developed tools for quantitative live imaging of axonal transport in peripheral nerves, for investigating axon degeneration mechanisms and for blocking axon degeneration genetically and pharmacologically when transport is impaired. Here, we will apply these to CIPN models to test whether axons can be permanently rescued, whether this is effective in vivo for a wider range of CIPN-inducing drugs, whether neuropathic pain is reduced, what this tells us about the degeneration mechanism and whether we can block this axon degeneration pharmacologically.

The potential non-academic beneficiaries of this project are:

(1) Pharma/biotech companies targeting axonal disorders in general and CIPN specifically. Axon degeneration is a significant event in most neurodegenerative diseases, including some which are highly prevalent and therefore represent major market opportunities for the commercial sector: Alzheimer's disease (lifetime risk 15%), stroke (15%), diabetic neuropathy (7%), glaucoma (2%) and Parkinson's disease (1.5%). Chemotherapy-induced peripheral neuropathy, a dose-limiting side effect of cancer treatments such as paclitaxel and vincristine, often resulting in lifelong pain is the major potential application of this knowledge. There is currently no effective method to prevent this axon loss and this application has clear therapeutic potential in this area. As explained in 'pathways to impact' we will actively engage the commercial sector to ensure this potential is realized.

(2) Patients with neurodegenerative disorders and cancer survivors. Prophylactic treatment during cancer chemotherapy should be able to prevent the occurrence of CIPN sparing up to several million cancer survivors worldwide from lifelong pain. It may also boost the efficacy of cancer treatment itself by allowing higher or longer doses before this limiting side effect appears. In most neurodegenerative disease, when axons fall below a threshold number every additional axon lost increases the severity of symptoms. Thus, a prophylactic therapy for multiple sclerosis relapses or progressive MS, or other disorders could also have a major impact on their future quality of life.

(3) Lay public interested in nervous system function. In our public engagement activities we find a strong interest in the nervous system among the lay public. While there is only a limited amount that individuals can do about the health of their nervous system, understanding what goes wrong can at least help some patients to come to terms with it, and motivates some healthy individuals to ensure they avoid a lifestyle that places strains on axon survival (e.g., excessive alcohol consumption, obesity, drug abuse).