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The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions

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Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder arising from mutations in the TSC1 or TSC2 genes. The resulting over-activation of the mammalian target of rapamycin (mTOR) signalling pathway leaves patients with TSC susceptible to the growth of non-malignant tumours in multiple organs. Previously, surgery was the main therapeutic option for TSC. However, pharmacological therapy with mTOR inhibitors such as everolimus and sirolimus is now emerging as an alternate approach. Everolimus and sirolimus have already been shown to be effective in treating subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML), and everolimus is currently being evaluated in treating TSC-related epilepsy. In November 2013 a group of European experts convened to discuss the current options and practical considerations for treating various manifestations of TSC. This article provides evidence-based recommendations for the treatment of SEGA, TSC-related epilepsy and renal AML, with a focus on where mTOR inhibitor therapy may be considered alongside other treatment options. Safety considerations regarding mTOR inhibitor therapy are also reviewed. With evidence of beneficial effects in neurological and non-neurological TSC manifestations, mTOR inhibitors may represent a systemic treatment for TSC.

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Acknowledgments

The authors wish to acknowledge the expert contribution from Dr. De Wit (Erasmus MC, Rotterdam, The Netherlands) attending the VEnice Network In Clinical Excellence Masterclass meeting.

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Authors and Affiliations

  1. Department of Neurosciences, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital of Rome, Rome, Italy

    Paolo Curatolo & Romina Moavero

  2. National Center for Rare Epilepsy-related Disorders, National Center of Epilepsy, Oslo University Hospital, Oslo, Norway

    Marit Bjørnvold

  3. Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital Basel, University of Basel, Basel, Switzerland

    Patricia E. Dill

  4. INSERM Unité 1511, Paris, France

    Patricia E. Dill

  5. Neuro Pediatra, Centro Hospitalar Lisboa Ocidental, Hospital São Francisco Xavier, Lisbon, Portugal

    José Carlos Ferreira

  6. Department of Paediatrics, University Hospital Vienna, Vienna, Austria

    Martha Feucht

  7. Diagnose und Behandlungszentrum für Kinder und Jugendliche, Vivantes Klinikum Neukölln, Berlin, Germany

    Christoph Hertzberg

  8. Pediatric Neurology Unit-UZ Brussel, Brussels, Belgium

    Anna Jansen

  9. Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland

    Sergiusz Jóźwiak

  10. Sussex Renal Unit, Royal Sussex County Hospital, Brighton, UK

    J. Christopher Kingswood

  11. The Trafford Department of Renal Medicine, Royal Sussex County Hospital, Brighton, UK

    J. Christopher Kingswood

  12. Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland

    Katarzyna Kotulska

  13. Servei de Neurologia Pediàtrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Alfons Macaya

  14. Pediatric Neurology Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Romina Moavero

  15. Department of Pediatric Neurology, Reference Centre for Rare Epilepsies and Tuberous Sclerosis Complex, Necker-Enfants Malades Hospital, University Paris Descartes, Paris, France

    Rima Nabbout

  16. University Medical Center Utrecht, Utrecht, The Netherlands

    Bernard A. Zonnenberg

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  1. Paolo Curatolo
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  2. Marit Bjørnvold
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  3. Patricia E. Dill
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  4. José Carlos Ferreira
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Correspondence to Paolo Curatolo.

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Funding

The VEnice Network in Clinical Excellence Masterclass meeting organized and supported by Novartis, formed the basis for this publication. The authors are fully responsible for the content of this manuscript. Medical writing support used for this article in terms of final editing and formatting of the draft manuscript was provided by Excerpta Medica, funded by Novartis, and none of the authors received any funding for the preparation of this manuscript. The work of PC, AJ, KK, SJ, RN, MF, CH, RM was partially supported by the Seventh Framework Programme of European Commission within the Large-scale Integrating Project EPISTOP (Proposal No: 602391-2).

Conflict of interest

PC was on the study steering committee of EXIST-1 and 3 trials funded by Novartis. He is also on the Scientific Advisory Board of TOSCA, a natural history study of tuberous sclerosis, funded by Novartis, and has received honoraria from Novartis for participation in advisory board meetings. MB is the national coordinator (Norway) of the EXIST-1 trial and TOSCA (international disease registry of tuberous sclerosis), funded by Novartis. PED has received consulting fees from Novartis. JCF has received honoraria and support from Novartis for travel to the VENICE (VEnice Network In Clinical Excellence) TSC Masterclass in 2013. MF has received honoraria and travel support from Novartis, Cyberonics, UCB and Eisai. CH declares that he received an honorarium for his participation, and travel funding from Novartis, for the TSC meeting in 2013. AJ is a member of the Scientific Advisory Board of TOSCA, a natural history study of tuberous sclerosis, funded by Novartis, and has received honoraria from Novartis for her participation in advisory board meetings. SJ was on the study steering committee of EXIST-1 trial funded by Novartis. He is also on the Scientific Advisory Board of TOSCA, a natural history study of tuberous sclerosis, funded by Novartis, and has received honoraria from Novartis for participation in advisory board meetings. JCK has received support for presenting his research at international meetings and manuscript publication about findings from his research from Novartis. He has received honoraria for his advisory work and presentations from Novartis. Dr. Kingswood’s institution has received research grants from Novartis, for which Dr. Kingswood was a Principal Investigator. KK has received speaker’s honoraria from Novartis. AM is a member of the TOSCA Scientific Advisory Board, funded by Novartis. He has received payment from Novartis for lectures and participation in advisory board meetings. RM has received a consulting fee from Novartis. RN was on the study steering committee of EXIST 3 trials funded by Novartis. She is also on the Scientific Advisory Board of TOSCA, a natural history study of tuberous sclerosis, funded by Novartis, and has received honoraria from Novartis for participation in advisory board meetings. She has also received speaker’s honoraria from Eisai, Nutricia, Zogenix and Shire. BAZ has received funding for research, as well as consulting and speaking fees, from Novartis.

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Curatolo, P., Bjørnvold, M., Dill, P.E. et al. The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions. Drugs 76, 551–565 (2016). https://doi.org/10.1007/s40265-016-0552-9

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