Clinical Impact of mTOR Inhibitors on the Management of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic disorder with an estimated prevalence of one in 6000, affecting approximately 1–2 million people worldwide irrespective of age, gender, and race [1]. The earliest modern description of the disorder was made by von Recklinghausen in 1862 [2]. In 1881, Bourneville provided a more detailed description and characterization of the peculiar hardened, discrete nodules in the brain and kidneys of a patient with vascular papular lesions of the face, mental retardation, and severe epilepsy, and was the first to name it “tuberous sclerosis” [3]. The constellation of facial lesions, cognitive impairment, and epilepsy comprised the first clinical diagnostic criteria for TSC established in 1908 by Vogt [4]. We now know, largely through the early work of Gomez in the latter part of the 20th century, that the majority of patients with TSC do not manifest all three components of Vogt’s triad, and that the disorder affects much more than just the brain and kidneys [5]. Indeed, individuals can experience hamartomatous lesions in every organ system of the body, including the heart (cardiac rhabdomyomas), lungs (pulmonary lymphangioleimyomatosis), and kidneys (renal angiomyolipomas). Although these lesions are typically benign with little malignant or metastatic potential, they can still be the source of significant morbidity and mortality in patients with TSC. The greatest morbidity and mortality are attributable to those lesions affecting the brain.Cerebral manifestations include subependymal nodules (SENs), cortical and subcortical tubers, and subependymal giant cell astrocytomas (SEGAs). SEGAs are problematic in that they can lead to progressive obstructive hydrocephalus and death [6]. Surgical resection of SEGAs has been the mainstay of treatment, but emerging evidence supports medical management with mammalian target of rapamycin (mTOR) inhibitors as a viable alternative. mTOR is a key intracellular protein present in all cells, and is part of two different regulatory complexes, referred to as mTORC1 and mTORC2 [7]. In patients with TSC, one of two TSC genes, TSC1 (hamartin) or TSC2 (tuberin), is deficient or defective [8]. As a result, mTOR is overly active and protein synthesis unchecked