Abstract
BackgroundTuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.MethodsWe completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.Results36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).ConclusionsSirolimus 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. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Trial RegistrationClinicaltrials.gov NCT00126672
Highlights
Tuberous sclerosis (TSC) is a tumor suppressor gene disorder characterized by the development of benign tumors in multiple organs [1]
TSC patients can have a number of medical problems including epilepsy, cognitive impairment, behavioral disorders, brain lesions, kidney angiomyolipomas, kidney cysts, early onset kidney cancer, skin tumors, cardiac tumors and pulmonary abnormalities including lymphangioleiomyomatosis (LAM) [6,7,8]
In addition to the primary endpoints evaluating safety and kidney angiomyolipoma response, we investigated the utility of mammalian target of rapamycin (mTOR) inhibitor treatment for many common clinical features of TSC by collecting secondary endpoint data on liver angiomyolipomas, subependymal giant cell astrocytomas (SEGAs), tubers, subependymal nodules (SENs), seizures, skin lesions, renal cysts, kidney function, and lung function in those individuals with LAM
Summary
Tuberous sclerosis (TSC) is a tumor suppressor gene disorder characterized by the development of benign tumors (hamartomas) in multiple organs [1]. It is an autosomal dominant disorder with high penetrance but variable expression, and the majority (60– 70%) of newly diagnosed individuals have a spontaneous mutation. TSC patients can have a number of medical problems including epilepsy, cognitive impairment, behavioral disorders, brain lesions (tubers, subependymal nodules and subependymal giant cell astrocytomas), kidney angiomyolipomas, kidney cysts, early onset kidney cancer, skin tumors (facial angiofibromas), cardiac tumors (rhabdomyomas) and pulmonary abnormalities including lymphangioleiomyomatosis (LAM) [6,7,8]. Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2
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