title: Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/-Mice Is Superior to Everolimus Alone.
abstract: Tuberous sclerosis (TSC) is an inherited tumor syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumors in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC-associated tumors including renal angiomyolipomas. However, tumor responses are usually only partial, and regrowth occurs after drug withdrawal. TSC-associated tumors are highly vascular, and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor (VEGF) A and VEGFD. Sorafenib inhibits multiple kinases including VEGF receptors and has been used to treat metastatic epithelioid angiomyolipoma in one case, but formal trials have not been undertaken. In this study, we investigated tumor angiogenesis and the therapeutic efficacy of everolimus in combination with sorafenib for renal tumors in Tsc2+/-mice. We found that these tumors exhibited remarkably variable angiogenesis despite consistent aberrant activation of mTOR and increased expression of HIF1α and VEGFA. Treatment of 11-month-old Tsc2+/-mice for 2 months with a combination of everolimus and sorafenib significantly reduced the number and size of solid renal tumors, whereas everolimus or sorafenib alone did not. These results suggest that inhibition of mTOR and multiple kinases including VEGF receptors using combination therapy could hold promise for the treatment of TSC-associated tumors that have responded inadequately to a rapalog alone.
authors.affiliation: Institute of Medical Genetics, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Medical Genetics, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Paulina A
authors.initials: PA
authors.lastname: Samsel
authors.affiliation: Institute of Medical Genetics, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Kalin
authors.initials: K
authors.lastname: Narov
authors.affiliation: Institute of Medical Genetics, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Jones
authors.affiliation: Warwick CTU, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gallacher
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gallacher
authors.affiliation: Institute of Medical Genetics, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: Institute of Medical Genetics, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Electronic address: shenmh@cf.ac.uk.
authors.forename: Ming Hong
authors.initials: MH
authors.lastname: Shen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage / Q000494:pharmacology*; D020690:GTPase-Activating Proteins / Q000235:genetics; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D014402:Tuberous Sclerosis / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; D010671:Phenylurea Compounds; C095637:RALBP1 protein, human; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib