Subependymal Giant Cell Astrocytomas

Franz, David Neal; Krueger, Darcy A.; Balko, M. Gregory

doi:10.1002/9783527630073.ch11

Cited by 6 publications

(2 citation statements)

References 44 publications

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“…Significant numbers of TSC patients develop progressive brain subependymal giant cell astrocytoma (SEGA) (4), renal angiomyolipoma (5), and/or pulmonary lymphangioleiomyomatosis (LAM) (6, 7). All three of these tumors can be life-threatening due to progressive disease development, and require therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Equivalent Benefit of Rapamycin and a Potent mTOR ATP-Competitive Inhibitor, MLN0128 (INK128), in a Mouse Model of Tuberous Sclerosis

Guo

Kwiatkowski

2013

Molecular Cancer Research

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Tuberous sclerosis complex (TSC) is a hamartoma syndrome in which brain, renal and lung tumors develop and cause both morbidity and death. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1. Rapamycin and related drugs have been shown to have clinical benefit for these tumors in TSC patients and those with sporadic forms of TSC-related neoplasms. However, lifelong therapy appears to be required, as tumors are not eliminated by this treatment. We examined the potential benefit of MLN0128, a novel potent mTOR ATP-competitive inhibitor, as a therapeutic strategy for renal cystadenomas that develop in A/J Tsc2+/− mice. Rapamycin given by intraperitoneal injection at 3 mg/kg 3 times per week, and MLN0128 given by gavage at 0.75 mg/kg 5 times per week had equivalent effects in suppressing tumor development during a 4 week treatment period, with an approximate 99% reduction in microscopic tumor cell volume. Marked reduction in activation of mTORC1, and blockade of cell growth was seen with both drugs, while only MLN0128 treatment had effects in blocking mTORC2 and 4EBP1 phosphorylation. However, when either drug was discontinued and mice were observed for two additional months, there was dramatic recovery of tumor growth, with extensive proliferation. Hence, long-lasting tumor growth control is not achieved with transient treatment with either drug, and MLN0128 and rapamycin have equivalent therapeutic benefit in this mouse model. Differences in side-effect profiles might make MLN0128 more attractive for treatment of patients with TSC-related tumors, but will require additional study in humans.

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Section: Introductionmentioning

confidence: 99%

Equivalent Benefit of Rapamycin and a Potent mTOR ATP-Competitive Inhibitor, MLN0128 (INK128), in a Mouse Model of Tuberous Sclerosis

Guo

Kwiatkowski

2013

Molecular Cancer Research

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“…Although regulatory approval of mTOR inhibitors is for four distinct manifestations of the disease (giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy) but since mTOR inhibitors address the underlying molecular defect in TSC, therapeutic effects can be expected for multiple aspects of the patient's condition. 17 The antiproliferative effects of sirolimus have been attributed to antiangiogenesis through vascular endothelial growth factor and antagonism of mTOR, as well as apoptosis. These may play a therapeutic role in the patients with vascular malformations.…”

Section: Discussionmentioning

confidence: 99%

Limb Hypertrophy—An Uncommon Presentation Yet a Common Link among Neurocutaneous Syndromes: A Series of Three Cases

Agrawal

Budania

Saini

et al. 2022

Journal of Pediatric Neurology

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Rapamycin and rapalogs for tuberous sclerosis complex

Sasongko

Ismail

Zabidi-Hussin

2016

Cochrane Database of Systematic Reviews

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We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.

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Subependymal Giant Cell Astrocytomas

Cited by 6 publications

References 44 publications

Equivalent Benefit of Rapamycin and a Potent mTOR ATP-Competitive Inhibitor, MLN0128 (INK128), in a Mouse Model of Tuberous Sclerosis

Equivalent Benefit of Rapamycin and a Potent mTOR ATP-Competitive Inhibitor, MLN0128 (INK128), in a Mouse Model of Tuberous Sclerosis

Limb Hypertrophy—An Uncommon Presentation Yet a Common Link among Neurocutaneous Syndromes: A Series of Three Cases

Rapamycin and rapalogs for tuberous sclerosis complex

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