Rapamycin causes regression of astrocytomas in tuberous sclerosis complex

Franz, David Neal; Leonard, Jennifer; Tudor, Cynthia; Chuck, Gail; Caré, Marguerite M.; Sethuraman, Gopalan; Dinopoulos, Argirios; Thomas, George; Crone, Kerry R.

doi:10.1002/ana.20784

Cited by 573 publications

(406 citation statements)

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“…These effects suggest that rapamycin may have effects on neuronal function but that enhanced neuronal excitability is not a consequence of rapamycin treatment. The results of a recent pilot study on five patients with TSC treated with rapamycin which demonstrated a regression of astrocytomas supported this assumption (Franz et al, 2006). In view of planned larger human trials evaluating rapamycin to slow or prevent formation of tubers in TSC patients, it was important to confirm this "no effect" hypothesis.…”

Section: Discussionmentioning

confidence: 92%

“…One group recently reported rapamycin-induced regression of astrocytomas in five patients with TSC. Four of these patients remained seizure-free during the treatment period; no information is given on seizure frequency of the fifth patient or on other neurological side effects (Franz et al, 2006). In the light of planned clinical trials for rapamycin in young patients, we investigated the effect of rapamycin on cell morphology, gene expression, and seizure-like firing patterns in cultured rat hippocampal neurons at postnatal time periods using morphometry, single cell mRNA amplification, and single unit recoding.…”

Section: Introductionmentioning

confidence: 99%

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Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

et al. 2007

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SummaryPurpose-We assayed the effects of rapamycin, an immunomodulatory agent known to inhibit the activity of the mammalian target of rapamycin (mTOR) cascade, on candidate gene expression and single unit firing properties in cultured rat hippocampal neurons as a strategy to define the effects of rapamycin on neuronal gene transcription and excitability.Methods-Rapamycin was added (100 nM) to cultured hippocampal neurons on days 3 and 14. Neuronal somatic size and dendritic length were assayed by immunohistochemistry and digital imaging. Radiolabeled mRNA was amplified from single hippocampal pyramidal neurons and used to probe cDNA arrays containing over 100 distinct candidate genes including cytoskeletal element, growth factor, transcription factor, neurotransmitter, and ion channel genes. In addition, the effects of rapamycin (200 nM) on spontaneous neuronal activity and voltage-dependent currents was assessed.Results-There were no effects of rapamycin on cell size or dendrite length. Rapamycin altered expression of distinct mRNAs in each gene family on days 3 and 14 in culture. Single unit recordings from neurons exposed to rapamycin exhibited no change from baseline. When spontaneous activity was increased by blocking GABA-mediated inhibition with bicuculline, a fraction of the neurons exhibited a decreased duration of spontaneous bursts and a decrease in synaptic inputs. Rapamycin did not appear to alter voltage dependent Na+ or K+ currents underlying action potentials.Conclusions-These data demonstrate that rapamycin does not produce neurotoxicity nor alter dendritic growth and complexity in vitro and does not significantly alter voltage gated sodium and potassium currents. Rapamycin does affect neuronal gene transcription in vitro. Use of rapamycin in clinical trials for patients with tuberous sclerosis complex should involve vigilance for possible effects on seizure frequency and neurocognitive function.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

et al. 2007

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“…The first case report of rapamycin-therapy for TSCassociated tumors in patients has been published in 2006 (Franz et al, 2006). Four TSC-patients with SEGAs and one with a pilocytic astrocytoma were treated with oral rapamycin at standard immunosuppressive doses (serum levels 5-15 ng/ml) for 2.5-20 months.…”

Section: The Mtorc1 Inhibitors As Treatment For Tscmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…Only one ‘professional’ raised the prospect of syndrome‐specific medication, highlighting the treatment of brain tumours in tuberous sclerosis (Franz et al . 2006), a breakthrough that this respondent saw as likely to extend people's lives and dramatically improve their well‐being. That only one respondent drew attention to the advance in syndrome‐specific medication may reflect our small sample size but also it may signal the belief that neurodevelopmental conditions are essentially incurable.…”

Section: Stakeholder Views On the Utility Of Syndrome‐specific Knowledgementioning

confidence: 99%

“…Of possibly more immediate benefit is the development of pharmaceuticals that have the potential to shrink the tumours associated with tuberous sclerosis (Franz et al . 2006). With respect to studies of behavioural, as opposed to the physical phenotypes, research suggests that what appear to be ostensibly similar behaviours – self‐injury, temper tantrums and aggression – might have entirely different causes (Oliver et al .…”

Section: Introductionmentioning

confidence: 99%

Improving the Health and Well‐Being of Adults With Conditions of a Genetic Origin: Views from Professionals, Syndrome Support Groups and Parents

Redley

Pannebakker

Holland

2016

Research Intellect Disabil

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BackgroundAdvances in medical genetics herald the possibility that health and social care services could be more responsive to the needs arising from a person's genotype. This development may be particularly important for those men and women whose learning disability (known internationally as intellectual disability) is linked to a neurodevelopmental condition of genetic origin.MethodThis possibility is tested through interviews with samples of (i) professional ‘opinion former’ with nationally recognised clinical and/or academic interests in learning disabilities and genetics; (ii) representatives of syndrome organisations prompting the interests of families where someone has a neurodevelopmental condition, and parent‐members of these same organisations.ResultsThe reporting and discussion of the interview data considers the possibility that notwithstanding the successes of the social model of disability, the health and wellbeing of people whose learning disability is associated with a neurodevelopmental condition could be better served by a more medicalised approach to their interests.ConclusionWhile a more medicalised approach to this populations’ disabilities would appear to be beneficial, so long as it is focused on interventions to improve their lives rather than catalogues their deficiencies.

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Rapamycin causes regression of astrocytomas in tuberous sclerosis complex

Abstract: Oral rapamycin therapy can induce regression of astrocytomas associated with TSC and may offer an alternative to operative therapy of these lesions.

Cited by 573 publications

References 31 publications

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Improving the Health and Well‐Being of Adults With Conditions of a Genetic Origin: Views from Professionals, Syndrome Support Groups and Parents

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