TSC clinical trials

In our last conference summary, it was noted that a number of clinical trials are underway to find an effective treatment for tuberous sclerosis complex (TSC). These trials use the mTORC1 inhibitors rapamycin and everolimus to compensate for mutations in the TSC1 and TSC2 genes. The results of one such trial have recently been reported by Dabora et al. (2011), and they show that treatment with rapamycin (which is also known as sirolimus) causes the regression of a number of tumours in TSC, such as kidney angiomyolipomas. Furthermore, VEGF-D was identified as a novel biomarker which could be used to monitor the size of these kidney angiomyolipomas over time.

The primary aim of this trial was to evaluate the effect of daily rapamycin treatment on kidney angiomyolipomas, and 36 adults (with at least one TSC-associated kidney angiomyolipoma) were recruited at six clinical sites across the US. In this study, it could be seen that almost half of the patients involved had a decrease in tumour size during the first 52 weeks of treatment. This treatment was reasonably tolerated, and no patients had progressive disease or complete regression. 13 subjects were then kept on rapamycin for a further year, and the difference between the numbers of patients showing a response, versus stable and progressive disease, was significant when compared to those not treated for an additional year.

As a secondary objective, it was noted that there was regression of TSC-associated liver angiomyolipomas and brain tumours (known as subependymal giant cell astrocytomas). Additionally, stable lung function was observed in those with TSC/LAM, and subjective improvements in TSC-associated skin lesions were also seen. However, the authors did not observe any significant changes in TSC-associated tubers, subependymal nodules or seizures.

As a whole, the results from Dabora et al. (2011) correlate well with similar mTOR inhibitor studies (Bissler et al., 2008; Krueger et al., 2010; Davies et al., 2011; McCormack et al., 2011). In addition, the authors noted a novel correlation between the levels of VEGF-D and kidney angiomyolipoma size. Accordingly, this biomarker could be used to monitor kidney angiomyolipomas during the treatment of TSC and in future clinical trials. Could a similar biomarker be found for BHD syndrome?

In summary, the results from this study indicate that rapamycin could be used to treat certain symptoms of TSC. It should be noted that pre-clinical rodent models have been crucial in enabling such studies to get to this stage, and a number of BHD models have been developed which could be utilised in a similar manner. However, the functional role of FLCN in mTOR signalling is still subject to some debate, as several recent publications have reported differing impacts on phosphorylated ribosomal protein S6 (an indicator of mTOR activation) when FLCN expression is reduced (click here for more information). Nevertheless, a clinical trial testing topical rapamycin for the treatment of fibrofolliculomas is currently under way – for more details about this and other trials which may be applicable to those with BHD syndrome, please do visit our clinical trials page on BHDSyndrome.org.


  • Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, et al. (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358: 140–151. PMID: 18184959
  • Dabora SL, Franz DN, Ashwal S, Sagalowsky A, DiMario FJ Jr, Miles D, Cutler D, Krueger D, Uppot RN, Rabenou R, Camposano S, Paolini J, Fennessy F, Lee N, Woodrum C, Manola J, Garber J, Thiele EA. (2011) Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One. 6(9): e23379. PMID: 21915260
  • Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, et al. (2011) Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 trial. Clin Cancer Res. 17(12): 4071-81. PMID: 21525172
  • Krueger DA, Care MM, Holland K, Agricola K, Tudor C, et al. (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New England Journal of Medicine 363: 1801–1811. PMID: 21047224
  • McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, et al. (2011) Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis. N Engl J Med. 364(17): 1595-606. PMID: 21410393
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.
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