Premium
Combination of a rapamycin analog (CCI‐779) and interferon‐γ is more effective than single agents in treating a mouse model of tuberous sclerosis complex
Author(s) -
Lee Laifong,
Sudentas Paul,
Dabora Sandra L.
Publication year - 2006
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.20357
Subject(s) - tuberous sclerosis , tsc2 , tsc1 , sirolimus , pi3k/akt/mtor pathway , cancer research , medicine , interferon , cytokine , cell growth , combination therapy , genetic enhancement , signal transduction , immunology , pharmacology , biology , pathology , gene , biochemistry , genetics
Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease‐causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon‐gamma (IFN‐γ) is another potential therapeutic agent for TSC. A high‐expressing IFN‐γ allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN‐γ reduces the severity of TSC‐related disease in mouse models. Here, we examine the effects of treating tumor‐bearing nude mice with a combination of a rapamycin analog (CCI‐779) and IFN‐γ. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI‐779 plus IFN‐γ had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI‐779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC‐related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC. © 2006 Wiley‐Liss, Inc.