What is the efficacy of sirolimus for the treatment of tuberous sclerosis complex (TSC)?

Updated: Aug 21, 2018
  • Author: David Neal Franz, MD; Chief Editor: Amy Kao, MD  more...
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Animal studies have demonstrated the ability of sirolimus to inhibit the aberrant growth of TSC-deficient cells in vitro and to induce apoptosis of renal tumors in animal models of TSC. A clinical trial of sirolimus for renal angiomyolipomas (AMLs) associated with tuberous sclerosis or lymphangioleiomyomatosis (LAM) published in 2008 by Bissler et al in the New England Journal of Medicine revealed an almost 50% decrease in AML volumes by the end of the 12-month sirolimus administration period. There were also improvements in forced expiratory volume (FEV1), forced vital capacity (FVC) and residual volume (RV) in patients with pulmonary LAM. Although some of these benefits were lost when sirolimus was discontinued, the therapy demonstrates the targeted effects of sirolimus on mTOr within the context of tuberous sclerosis and provides promise as a palliative and future treatment strategy in these conditions. [16]

A phase 2 multicenter trial evaluated the efficacy and tolerability of the mTOr inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Thirty-six adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4%; 47.2% had stable disease and 8.3% were not evaluable. The mean decrease in kidney tumor size was 29.9%. Kidney angiomyolipomas regrew when sirolimus was discontinued, but responses persist if treatment was continued after week 52. Regression of brain tumors (subependymal giant cell astrocytomas [SEGAs]) in 7 of 11 cases, regression of liver angiomyolipomas in 4 of 5 cases, subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM were also noted. A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size. [17]

Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size.

Sirolimus is thought to cross the blood-brain barrier to a limited, but unknown, extent. Regression of SEGAs in association with oral rapamycin therapy was reported. [18] This observation, while encouraging, required further study to confirm both the effect of mTOR inhibitors and their appropriate use in the treatment of giant cell astrocytomas.

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