Identifying novel drugs to treat neurofibromatosis tumours using a unique combinatorial screening strategy

The aim of this project is to find new ways of treating a disease called Neurofibromatosis type 1 (NF1). NF1 is a common disease affecting approximately one in every three thousand people worldwide. People with NF1 suffer from a variety of symptoms including spots on the skin, learning difficulties, bone deformities and lumps under the skin. These lumps are due to tumours growing along nerves, which can turn into more aggressive cancers, often leading to death. Symptoms generally start in early childhood and continue throughout life.

One of the fastest and safest ways to find a new treatment for a disease is to repurpose existing medicines that are already used to treat other diseases. These medicines are already known to be safe for use in humans and can be quickly developed for the treatment of a new disease. Our research focusses on developing new methods that allow us to efficiently identify existing drugs that can be repurposed in this way. In previous studies, our methods have already been used to identify candidate drugs for two other diseases.

There is currently no effective drug available to treat NF1. In this project, we will search for existing drugs that will effectively kill NF1 tumour cells without killing healthy cells. To improve our chances of finding an effective treatment, we will also test combinations of drugs to find those that act together to more efficiently kill NF1 tumour cells. Medicines are often more effective at treating a disease when two drugs are combined together into a single treatment. However, it can be very challenging to identify effective combinations of drugs because of the large number of possible drug pairs that must be tested. Using a new method that we have recently developed, called high-throughput Variable Dose Analysis (htVDA), we can test pairs of drug targets very quickly and therefore have a high chance of finding an effective combination.

Finally, by studying the interactions between candidate drug targets, we can gain insight into the genes and molecular pathways that are important for the development of NF1 disease. This will lead to new hypotheses to inform future studies and new therapeutic strategies relevant to NF1.

At the end of the project, we expect to have found drugs that can be used alone or in combinations to specifically kill NF1 mutant cells. These new candidates can then be tested further to develop powerful new treatments for people with NF1. By focussing on repurposing existing drugs our results will be rapidly transferrable to clinical use to treat NF1 patients in the near future.

Neurofibromatosis type 1 (NF1) is a common genetic disease associated with tumour formation along nerves. The tumours cause a variety of symptoms and can progress into malignant cancers that often result in death. Previous studies have used genetic and compound screens to find candidate drugs for the treatment of NF1 tumours. However, few drugs have emerged and none have yet progressed to clinical use.

Our research is focussed on developing novel approaches to genetic screens that greatly improve the chances of identifying effective drug candidates. Using an earlier version of our new methods, existing drugs have already been identified that can be repurposed to treat tuberous sclerosis complex and Vhl-linked kidney cancer, illustrating the power of our screening approach.

The aim of this proposal is to apply our new screening methods to find existing drugs that can be used alone or in combinations to effectively kill NF1 tumour cells without affecting healthy cells.

We have identified 46 candidate drug targets using genetic screens in Drosophila cells. Furthermore, we have validated two candidates in human cells and a mouse model. In this project, we will first filter the results of the Drosophila screen by testing the candidates in a panel of human NF1 model cell lines. This cross-species filter will identify candidates that kill NF1 mutant cells in diverse genetic contexts, therefore increasing the chance of successful translation to clinical use. In addition, we will apply a new method called high-throughput Variable Dose Analysis (htVDA) to rapidly and accurately assess pairwise combinations of genetic and pharmacological treatments. This will identify pairs of existing drugs that can be repurposed for combinatorial treatment of NF1 tumours.

This combination of novel approaches will allow us to identify new candidate treatments for NF1 that have a high chance of translation to clinical use.