title: Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models.
abstract: Tuberous sclerosis complex (TSC) is a familial tumor disorder for which there is no effective medical therapy. Disease-causing mutations in the TSC1 or TSC2 gene lead to increased mammalian target of rapamycin (mTOR) kinase activity in the conserved mTOR signaling pathway, which regulates nutrient uptake, cell growth, and protein translation. The normal function of TSC1 and TSC2 gene products is to form a complex that reduces mTOR kinase activity. Thus, mTOR kinase inhibition may be a useful targeted therapeutic approach. Elevated interferon-gamma (IFN-gamma) expression is associated with decreased severity of kidney tumors in TSC patients and mouse models; therefore, IFN-gamma also has therapeutic potential. We studied cohorts of Tsc2+/- mice and a novel mouse model of Tsc2-null tumors in order to evaluate the efficacy of targeted therapy for TSC. We found that treatment with either an mTOR kinase inhibitor (CCI-779, a rapamycin analog) or with IFN-gamma reduced the severity of TSC-related disease without significant toxicity. These results constitute definitive preclinical data that justify proceeding with clinical trials using these agents in selected patients with TSC and related disorders.
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Laifong
authors.initials: L
authors.lastname: Lee
authors.forename: Paul
authors.initials: P
authors.lastname: Sudentas
authors.forename: Brian
authors.initials: B
authors.lastname: Donohue
authors.forename: Kirsten
authors.initials: K
authors.lastname: Asrican
authors.forename: Aelaf
authors.initials: A
authors.lastname: Worku
authors.forename: Victoria
authors.initials: V
authors.lastname: Walker
authors.forename: Yanping
authors.initials: Y
authors.lastname: Sun
authors.forename: Karl
authors.initials: K
authors.lastname: Schmidt
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Albert
authors.forename: Nisreen
authors.initials: N
authors.lastname: El-Hashemite
authors.forename: Alan S
authors.initials: AS
authors.lastname: Lader
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Onda
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Dabora
mesh_terms: D000818:Animals; D003537:Cystadenoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006391:Hemangioma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007371:Interferon-gamma / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D012097:Repressor Proteins; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C401859:temsirolimus; D007371:Interferon-gamma; D011494:Protein Kinases; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus