title: Therapeutic trial of metformin and bortezomib in a mouse model of tuberous sclerosis complex (TSC).
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.
authors.affiliation: Translational Medicine Division, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Auricchio
authors.forename: Izabela
authors.initials: I
authors.lastname: Malinowska
authors.forename: Reuben
authors.initials: R
authors.lastname: Shaw
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D004195:Disease Models, Animal; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D052177:Kidney Diseases, Cystic / Q000188:drug therapy / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008687:Metformin