Everolimus: in patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex

Adis, a Wolters Kluwer Business, Auckland, New Zealand.
Paediatric Drugs (Impact Factor: 1.98). 12/2011; 14(1):51-60.
Source: PubMed

ABSTRACT Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). Everolimus (starting dosage 3.0 mg/m(2)) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). At 6 months, 32% of patients treated with everolimus had a ≥50% reduction in the volume of their largest SEGA lesion (assessed via an independent central radiology review); 75% had a ≥30% reduction. No patients developed new lesions. During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus. In a phase III trial (EXIST-1) in 117 patients with SEGA associated with TSC, 35% of everolimus recipients (starting dosage 4.5 mg/m(2)) versus none of the placebo recipients (p < 0.0001) had an overall response (a reduction in the sum of all target SEGA volumes of ≥50% relative to baseline, nonworsening of non-target SEGA lesions, no new SEGA lesions, and no new/worsening hydrocephalus). Everolimus was generally well tolerated in patients with SEGA associated with TSC; most drug-related adverse reactions were mild to moderate in severity.

1 Follower
7 Reads
  • Source
    • "These successful preclinical studies have paved the way for many clinical trials for brain, kidney and lung manifestations of TSC [15] [41]. Recently, the FDA approved an additional indication for the rapalogue everolimus to treat refractory SEGAs associated with TSC [10] [17] [28]. However, in some cases the SEGAs are found to reemerge after discontinuation of everolimus treatment, and the consequences of long-term treatment with rapalogues remains unclear at this time. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The genetic disease tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by loss of function mutations in either TSC1 (hamartin) or TSC2 (tuberin), which serve as negative regulators of mechanistic target of rapamycin complex 1 (mTORC1) activity. TSC patients exhibit developmental brain abnormalities and tuber formations that are associated with neuropsychological and neurocognitive impairments, seizures and premature death. Mechanistically, TSC1 and TSC2 loss of function mutations result in abnormally high mTORC1 activity. Thus, the development of a strategy to inhibit abnormally high mTORC1 activity may have therapeutic value in the treatment of TSC. mTORC1 is a master regulator of growth processes, and its activity can be reduced by withdrawal of growth factors, decreased energy availability, and by the immunosuppressant rapamycin. Recently, glutamine has been shown to alter mTORC1 activity in a TSC1-TSC2 independent manner in cells cultured under amino acid- and serum-deprived conditions. Since starvation culture conditions are not physiologically relevant, we examined if glutamine can regulate mTORC1 in non-deprived cells and in a murine model of TSC. Our results show that glutamine can reduce phosphorylation of S6 and S6 kinase, surrogate indicators of mTORC1 activity, in both deprived and non-deprived cells, although higher concentrations were required for non-deprived cultures. When administered orally to TSC2 knockout mice, glutamine reduced S6 phosphorylation in the brain and significantly prolonged their lifespan. Taken together, these studies suggest that glutamine supplementation can be used as a potential treatment for TSC. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 01/2015; 457(4). DOI:10.1016/j.bbrc.2015.01.039 · 2.30 Impact Factor
  • Source
    • "mTOR is a key effector in the PI3K/Akt/mTOR pathway and it plays a critical role in regulating cell proliferation, survival, and angiogenesis [7]. Everolimus has been approved for the treatment of papillary renal carcinoma, pancreatic neuroendocrine tumor, some types of breast cancer, and subependymal giant cell astrocytoma associated with tuberous sclerosis [8] [9] [10] [11]. In HCC, a phase I/II study of everolimus has been conducted in patients with advanced HCC and "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60-87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC.
    02/2013; 2013:103830. DOI:10.1155/2013/103830
  • Source
    • "Both sirolimus and everolimus exert their inhibitory effects on mTOR-regulated processes by reducing the phosphorylation of downstream mTOR effectors, including the translational repressor eukaryotic elongation factor 4E binding protein 1 (4EBP1) and the S6 ribosomal protein kinase 1 (S6K1) [8] [19] [20]. This inhibitory effect disrupts S6K1 and 4EBP1 function, which are responsible for the translation of mRNA encoding pivotal proteins that are involved in cell cycle regulation, glycolytic activity, angiogenesis, cell size control, and cellular growth [8] [19] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.
    Current Neuropharmacology 12/2012; 10(4):404-15. DOI:10.2174/157015912804143595 · 3.05 Impact Factor
Show more