Premium
Efficacy of a rapamycin analog (CCI‐779) and IFN‐γ in tuberous sclerosis mouse models
Author(s) -
Lee Laifong,
Sudentas Paul,
Donohue Brian,
Asrican Kirsten,
Worku Aelaf,
Walker Victoria,
Sun Yanping,
Schmidt Karl,
Albert Mitchell S.,
ElHashemite Nisreen,
Lader Alan S.,
Onda Hiroaki,
Zhang Hongbing,
Kwiatkowski David J.,
Dabora Sandra L.
Publication year - 2005
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20118
Subject(s) - tsc2 , tsc1 , tuberous sclerosis , pi3k/akt/mtor pathway , cancer research , kinase , medicine , sirolimus , rptor , biology , signal transduction , pathology , microbiology and biotechnology
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‐γ) expression is associated with decreased severity of kidney tumors in TSC patients and mouse models; therefore, IFN‐γ 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‐γ 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. © 2004 Wiley‐Liss, Inc.