Effects of rapamycin in the Eker rat model of tuberous sclerosis complex.
Tuberous sclerosis complex (TSC) presents in the pediatric population with a constellation of benign tumors that affect the brain, heart, kidney, lung, and skin. No therapy has been shown to halt disease progression or to prevent its onset. The pathogenesis of TSC stems from the inactivation of one of the two TSC genes, TSC1 and TSC2. A key function of these genes is to regulate the mammalian target of rapamycin (mTOR) pathway in response to cellular energy and nutrient and growth factor availability. Consequently, TSC-related tumors exhibit uncontrolled activation of mTOR and its effectors. Previous work has shown that a specific mTOR inhibitor, rapamycin, effectively down-regulated mTOR activity in renal tumors of Eker rats that carry a germline Tsc2 mutation. Using this model, we investigated the effects of rapamycin on pituitary and renal tumors. We observed that rats with pituitary tumors had significantly shorter survival than those without pituitary pathology. Treatment with rapamycin effectively improved their clinical state and prolonged their survival. Rapamycin also resulted in a significant decrease in the size of the Tsc2-related renal tumors. In both types of pathology, tumor response was accompanied by down-regulation of ribosomal S6 kinase activity, reduction in cell size, and induction of apoptosis. Evidence for drug resistance was found in a small percentage of lesions after prolonged therapy. When rapamycin was given before onset of disease, subsequent development of macroscopic renal tumors was reduced, but no effect on the number of microscopic precursor lesions was found. We conclude that rapamycin-sensitive mTOR activity was critical to tumor progression in the Eker rat model, but rapamycin is unlikely to eradicate all disease as a result of the development of drug resistance. Our data also suggest the role of a rapamycin-insensitive pathway during tumor initiation.
Kenerson
Heidi
H
Department of Surgery, University of Washington, 1959 NE Pacific Street, Box 356410, Seattle, WA 98195, USA.
Dundon
Trevor A
TA
Yeung
Raymond S
RS
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D015151:Immunoblotting; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D009154:Mutation; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014402:Tuberous Sclerosis / Q000188:drug therapy*; D015854:Up-Regulation
D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus