Application of mTOR inhibitors as first line therapy for tuberous sclerosis-associated kidney disease

Identifying a new treatment pathway

Before the Cardiff University research, led by Professor Julian Sampson, all treatments for TSC-related renal tumours carried risks of immediate complications and permanent damage.

The university researchers showed that disease-causing genetic mutations in TSC patients resulted in altered mTOR signalling, a growth-regulating protein that affects cell growth, survival, metabolism, and immunity.

The discovery of the link between the TSC1/2 genes, mTOR signalling and tumour growth in TSC presented the possibility that TSC tumours could be treated with the existing drug rapamycin, rather than through surgery. Cardiff University researchers carried out studies to explore the broader implications of mTOR inhibition in mice, using both rapamycin and related mTOR inhibitors.

Subsequent clinical studies by the university team showed that mTOR inhibitors could be used as novel therapies for TSC, shrinking renal tumours and also helping to alleviate some of the wider disease symptoms.

Proving effectiveness via clinical trial

A clinical trial, called TESSTAL, was designed to assess the effectiveness and safety of rapamycin in treating TSC patients with renal tumours. The trial found that across two years, the renal tumour burden was reduced in all patients.

Of the 23 tumours treated, 21 shrank in size and 50% of patients had responses that saw a 30% or more reduction in the size of their tumours. The study also found that sustained treatment maintained the reduction in tumour size.

Establishing the use of inhibitors across patient groups

TSC patients may have a range of genotypes, with a variety of mutations in either TSC1 or TSC2. Prior to the research by the university team, it was not known whether patient responses to treatment with mTOR inhibitors depended on mutation.

In a joint study between Cardiff University and international collaborators, no correlation was seen between type of mutation and response to therapy, concluding that mTOR inhibitor therapy could be used across all TSC patients, regardless of their underlying genetics.

The university team’s rigorous investigation of mTOR signalling in the pathology and treatment of TSC provided important evidence needed to implement mTOR inhibitor therapy into the clinical management of the disease worldwide.