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-gamma) is another potential therapeutic agent for
TSC. A high-expressing IFN-gamma allele is associated with a lower frequency of kidney
tumors in
TSC patients, and treatment with exogenous IFN-gamma 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-gamma. 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-gamma 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.