Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
권호 표지
DOI QR코드

DOI QR Code

Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis

  • Kim, Won-Seop (Department of Pediatrics, Chungbuk National University, College of Medicine)
  • 투고 : 2011.04.19
  • 심사 : 2011.05.11
  • 발행 : 2011.06.15
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that results from mutations in the TSC1 or TSC2 genes, and is associated with hamartomas in several organs, including subependymal giant cell tumors. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. The TSC1- and TSC2-encoded proteins modulate cell function via the mammalian target of rapamycin (mTOR) signaling cascade, and are key factors in the regulation of cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. The mTOR pathway represents a logical candidate for drug targeting, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.

키워드

참고문헌

  1. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345-56. https://doi.org/10.1056/NEJMra055323
  2. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci 1991;615:125-7. https://doi.org/10.1111/j.1749-6632.1991.tb37754.x
  3. Lyczkowski DA, Conant KD, Pulsifer MB, Jarrett DY, Grant PE, Kwiatkowski DJ, et al. Intrafamilial phenotypic variability in tuberous sclerosis complex. J Child Neurol 2007;22:1348-55. https://doi.org/10.1177/0883073807307093
  4. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392-5.
  5. Reiling JH, Sabatini DM. Stress and mTORture signaling. Oncogene 2006;25:6373-83. https://doi.org/10.1038/sj.onc.1209889
  6. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY) 2009;1:281-8.
  7. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005;17:596-603. https://doi.org/10.1016/j.ceb.2005.09.009
  8. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007;12:112-24. https://doi.org/10.1016/j.drudis.2006.12.008
  9. Bolster DR, Crozier SJ, Kimball SR, Jefferson LS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through downregulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 2002;277:23977-80. https://doi.org/10.1074/jbc.C200171200
  10. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/ eIF4E. Genes Dev 2002;16:1472-87. https://doi.org/10.1101/gad.995802
  11. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-57. https://doi.org/10.1038/ncb839
  12. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37(Pt 1):217-22. https://doi.org/10.1042/BST0370217
  13. Shintani T, Klionsky DJ. Autophagy in health and disease: a doubleedged sword. Science 2004;306:990-5. https://doi.org/10.1126/science.1099993
  14. Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 2008;32: 329-39. https://doi.org/10.1016/j.nbd.2008.07.022
  15. Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia 2010;51:27-36.
  16. Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 2004;63:1457-61. https://doi.org/10.1212/01.WNL.0000142039.14522.1A
  17. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006;59:490-8. https://doi.org/10.1002/ana.20784
  18. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801-11. https://doi.org/10.1056/NEJMoa1001671
  19. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-51. https://doi.org/10.1056/NEJMoa063564
  20. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 2008;14:843-8. https://doi.org/10.1038/nm1788
  21. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 2008;28:5422-32. https://doi.org/10.1523/JNEUROSCI.0955-08.2008
  22. Koenig MK, Butler IJ, Northrup H. Regression of subependymal giant cell astrocytoma with rapamycin in tuberous sclerosis complex. J Child Neurol 2008;23:1238-9. https://doi.org/10.1177/0883073808321764
  23. Birca A, Mercier C, Major P. Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex. J Neurosurg Pediatr 2010;6:381-4. https://doi.org/10.3171/2010.7.PEDS10221
  24. Yalon M, Ben-Sira L, Constantini S, Toren A. Regression of subependymal giant cell astrocytomas with RAD001 (Everolimus) in tuberous sclerosis complex. Childs Nerv Syst 2011;27:179-81. https://doi.org/10.1007/s00381-010-1222-y
  25. Woodrum C, Nobil A, Dabora SL. Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors. J Transl Med 2010;8:14. https://doi.org/10.1186/1479-5876-8-14
  26. Lee N, Woodrum CL, Nobil AM, Rauktys AE, Messina MP, Dabora SL. Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol 2009;9:8.
  27. Moavero R, Cerminara C, Curatolo P. Epilepsy secondary to tuberous sclerosis: lessons learned and current challenges. Childs Nerv Syst 2010;26:1495-504. https://doi.org/10.1007/s00381-010-1128-8

피인용 문헌

  1. Topical rapamycin (sirolimus) for facial angiofibromas vol.4, pp.1, 2013, https://doi.org/10.4103/2229-5178.105488
  2. Retraction: Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis vol.56, pp.6, 2013, https://doi.org/10.3345/kjp.2013.56.6.269
  3. Recommendations for the radiological diagnosis and follow-up of neuropathological abnormalities associated with tuberous sclerosis complex vol.118, pp.2, 2011, https://doi.org/10.1007/s11060-014-1429-y
  4. Rapamycin therapy for neonatal tuberous sclerosis complex with cardiac rhabdomyomas: A case report and review vol.14, pp.6, 2011, https://doi.org/10.3892/etm.2017.5335