Abstract
Tuberous sclerosis complex (TSC) is a human genetic disorder in which loss of either TSC1 or TSC2 leads to development of hamartoma lesions, which can progress and be life-threatening or fatal. The TSC1/TSC2 protein complex regulates the state of activation of mTORC1. Tsc2+/− mice develop renal cystadenoma lesions which grow progressively. Both bortezomib and metformin have been proposed as potential therapeutics in TSC. We examined the potential benefit of 1 month treatment with bortezomib, and 4 month treatment with metformin in Tsc2+/− mice. Results were compared to vehicle treatment and treatment with the mTORC1 inhibitor rapamycin for 1 month. We used a quantitative tumor volume measurement on stained paraffin sections to assess the effect of these drugs. The median tumor volume per kidney was decreased by 99% in mice treated with rapamycin (p = 0.0004). In contrast, the median tumor volume per kidney was not significantly reduced for either the bortezomib cohort or the metformin cohort. Biochemical studies confirmed that bortezomib and metformin had their expected pharmacodynamic effects. We conclude that neither bortezomib nor metformin has significant benefit in this native Tsc2+/− mouse model, which suggests limited benefit of these compounds in the treatment of TSC hamartomas and related lesions.
Highlights
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which hamartomas develop in multiple organ systems, including the heart, brain, skin, kidneys, lymphatic system, and lungs [1]
GTP-RHEB is an essential activator of mTOR complex 1, with downstream effects on transcription and translation, cellular metabolism, autophagy, ribosome biogenesis, cell size control, and cell proliferation [4,5]. mTORC1 is constitutively activated in cells lacking either TSC1 or TSC2 and in hamartomas from TSC patients [6]
Cohorts of A/J strain Tsc2+/2 mice were treated with one of 5 regimens: 1) rapamycin given at 6 mg/kg IP three days per week (n = 9); 2) vehicle given on the same schedule (n = 5); 3) bortezomib given at 0.8 mg/kg SC two days per week (n = 8); 4) metformin given in 5% sucrose drinking water at 300 mg/kg per day (n = 10); and 5) 5% sucrose drinking water (n = 8)
Summary
TSC is an autosomal dominant tumor suppressor gene syndrome in which hamartomas develop in multiple organ systems, including the heart, brain, skin, kidneys, lymphatic system, and lungs [1]. Most lesions have a benign course, several can grow progressively necessitating clinical intervention with drug treatment and/or surgery. TSC is due to mutations in either TSC1 or TSC2, and progressive lesions typically show complete loss of one gene product or the other [1]. MTORC1 is constitutively activated in cells lacking either TSC1 or TSC2 and in hamartomas from TSC patients [6]. Rapamycin (sirolimus) and related drugs (everolimus), which bind to and inhibit mTORC1 through FKBP12, have shown clinical activity for treatment of several manifestations of TSC, including renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, and brain subependymal giant cell astrocytomas [7,8,9,10]. Rapamycin does not cause complete regression of disease in most instances, and cessation of treatment can lead to regrowth of hamartoma lesions [8]. A fraction of patients do not tolerate the drug, mainly due to oral mucositis [7,8,9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
