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Combination of everolimus with sorafenib for solid renal tumours in Tsc2+/- mice is superior to everolimus alone

Yang, Jian, Samsel, Paulina A., Narov, Kalin, Jones, Ashley, Gallacher, Daniel, Gallacher, John, Sampson, Julian Roy and Shen, Ming Hong 2017. Combination of everolimus with sorafenib for solid renal tumours in Tsc2+/- mice is superior to everolimus alone. Neoplasia 19 (2) , pp. 112-120. 10.1016/j.neo.2016.12.008

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Abstract

Tuberous sclerosis is an inherited tumour syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumours in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC-associated tumours including renal angiomyolipomas. However, tumour responses are usually only partial and regrowth occurs after drug withdrawal. TSC-associated tumours are highly vascular and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor A (VEGFA) 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 tumour angiogenesis and the therapeutic efficacy of everolimus in combination with sorafenib for renal tumours in Tsc2+/- mice. We found that these tumours 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 two months with a combination of everolimus and sorafenib significantly reduced the number and size of solid renal tumours, 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 tumours that have responded inadequately to a rapalog alone.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Tuberous sclerosis, renal tumours, mTOR, everolimus, sorafenib
Publisher: Elsevier
ISSN: 1522-8002
Funders: Tuberous Sclerosis Association, Wales Gene Park
Date of First Compliant Deposit: 20 December 2016
Date of Acceptance: 12 December 2016
Last Modified: 21 Aug 2019 02:14
URI: http://orca.cf.ac.uk/id/eprint/96874

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