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Conference reveals promising future research directions in TSC

Clare Stuart, ATSS Project Manager, recently attended the 2013 International Research Conference on Tuberous Sclerosis Complex and Related Disorders. Hosted by the TS Alliance, this conference was themed “Molecules to Medicines”. Clare’s travel was sponsored by TSC International.

It is very difficult to summarise a research conference in a short article. Instead, this article attempts to explain how the research presented at the conference may shape the way Tuberous Sclerosis is treated in the future.

2013 Res Conf Logo WebmTOR inhibitors, including sirolimus and everolimus, are new treatments that are helping many individuals with TSC. However, these new medicines are less than perfect treatments for two reasons:

1. They are partial – tumours do not disappear, they do not work well for all individuals with TSC

2. They are reversible – when the patient stops taking the medicine, tumours start to grow again.

The TSC research community are taking on the challenge of how to improve upon these limitations. Possible improvements could be using mTOR inhibitors earlier or in combination with another medicine. There also could be new medicines that could be given without an mTOR inhibitor.

A diverse range of studies were presented at the conference and this article provides only highlights from the 4 day event. Some themes of the conference were:

Understanding how TSC cells work

Many TSC researchers study the behaviour of cells, usually by growing these in a laboratory, manipulating the environment they grow in and measuring different chemicals being produced by these cells.

Some of this “basic science” work made new discoveries about both the mTOR and other protein pathways. Other work identified factors that influence how TSC cells grow, how they multiply and how they die. For example, one study manipulated how much oxygen and nutrients are available to the cell. This research is important because understanding more about how tumour cells work and the environment they grow in may help us to identify future treatments for TSC. Some of the research suggests possible compounds that could be investigated further. Much more work is needed before these are understood including testing these in animal models. This basic science work is important to give the research community future areas for research that may one day lead to new treatments for TSC.

Improving the tools used to study TSC such as mouse models

Animal models are useful in TSC to understand the causes of disease, variations within the disease and testing possible new treatments. Animals used in TSC research include drosophilia (fruit flies), zebra fish and mice. Some studies presented at the conference included the development of new mouse models. For example, the first mouse model of TSC that shows skin tumours.

Determining best way to treat with available therapies

Now that mTOR inhibitors are becoming available many researchers are considering questions about how and when to use these. There was discussion about how to determine when to use these medicines particularly for kidney AMLs and LAM.

A new direction in TSC research may be preventative trials of these medicines. These trials would involve children diagnosed with TSC that do not yet show any symptoms to consider whether these medicines have a preventative effect. There are significant ethical questions that need to be considered before such a trial could be run.

The EXIST-1 and EXIST-2 clinical trial examined the use of everolimus to treat SEGAs and kidney angiomyolipomas (AMLs) respectively. Updates from both trials showed no significant changes in either outcome (reduction in tumour size) or adverse events. The plans for EXIST-3 (studying the use of everolimus for a selected group of patients with refractory epilepsy) and for early studies into the use of everolimus for neurocognitive outcomes were also presented.

 Understanding more about the cases of TSC where no TSC gene mutation can be identified

Current genetic testing cannot find a TSC1 or TSC2 gene mutation in 10-15% of people already diagnosed with TSC. One of the studies presented at the conference found that in approximately half of these cases, next generation sequencing was able to identify a mutation. Another study showed that in some of these cases the TSC mutation is only in a portion of their cells, possibly originating in a type of cell called the neural crest cells.

Beyond the selection mentioned above, there was a wide variety of work presented at the conference and in the posters. This conference demonstrated that there is a strong pipeline of work in Tuberous Sclerosis and the wider TSC community can be confident that mTOR inhibitors are only the first wave of new treatments that will improve the lives of those living with TSC and get us closer to a cure.

A longer article about the conference will be published in Reach Out in November 2013.



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