125th Anniversary Scholarships for Black British Researchers – Identifying novel therapies to alleviate the neurotoxic side-effects of chemotherapy

Neurotoxicity is a major side-effect of chemotherapy drugs used to treat many common cancers, including bowel, breast and lung cancers. Patients commonly suffer from peripheral nerve pain, loss of feeling and sensation in the fingers and toes, hypersensitivity to both cold and heat. Patients also report cognitive effects, including loss of concentration and memory. Symptoms are often so extreme that drug doses have to be reduced or treatment curtailed. Symptoms occur acutely during treatment but can also build up over months and persist for months or years after the end of treatment with major impact on the quality-of-life for cancer survivors. There are currently no effective treatments to reduce either the peripheral neuropathy or cognitive effects.

In this project, the student will take a multi-system approach to test a novel therapeutic strategy with the potential to ameliorate both peripheral and central symptoms. We have shown that targeting the DNA damage response is neuroprotective in pre-clinical models of multiple different forms of neurological disease, including both acute and chronic disease. These neurological disorders all feature unrepaired DNA damage in neurons, which is also a feature of chemotherapy-induced neurotoxicity. Hence, it is possible that the same approach will prove to be neuroprotective and ameliorate the side-effects of chemotherapy.

In the first part of the project, the student will examine activity changes occurring in the brain following chemotherapy treatment. The student will culture neurons and organotypic slices from the cortexes of mice on multi-electrode arrays to examine the effect of chemotherapy drugs in both 2D and 3D brain networks. We will then try to block these changes using brain-penetrant inhibitors of the DNA damage response.

The second part of project will study the peripheral and cognitive effects of chemotherapy drugs on fruit flies by harnessing the power of Drosophila genetic screens to identify novel pathways acting downstream of the drugs. We have developed a robust short-term memory assay in Drosophila and can see that treatment with cisplatin results in a memory deficit reminiscent of the commonly reported cognitive effects in patients. Cisplatin also causes hypersensitivity to temperature, which mirrors one aspect of the peripheral neurotoxicity in patients. The student will use optogenetics to acutely inhibit or activate specific classes of neuron in the learning centres of the Drosophila brain and in the nociceptive sensory neurons in the peripheral nervous system. These techniques, coupled with the precision genetics of Drosophila will allow the student to knockdown expression of key DNA damage response components and candidate downstream effectors to identify which pathways downstream of DNA damage are mediating the neurotoxicity.

In the final part of the project, the student will use a combination of existing transcriptomics data and targeted Western blotting to analyse key changes in cultured dorsal root ganglia neurons exposed to chemotherapy drugs and co-administered with inhibitors of the DNA damage response. Together with the first two projects, this approach will help us understand the neuroprotective effect of the DNA damage response inhibitors and potentially identify new drug targets for neuroprotection.

You can find more information here: 125th Anniversary Scholarships for Black British Researchers – University of Birmingham