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.

Combination Treatment With Sorafenib and Everolimus Regresses a Doxorubicin-resistant Osteosarcoma in a PDOX Mouse Model

“…EVL has been shown to increase the activity of SFN by targeting different intracellular targets and can reverse resistance to SFN. Synergistic interactions between SFN and EVL have been shown in studies of several cancers such as renal, hepatic, and pancreatic cancers (4)(5)(6)(7)(9)(10)(11).…”

“…However, recurrent and progressive osteosarcoma is a recalcitrant disease. Sorafenib (SFN), an inhibitor of various tyrosine protein kinases (2,3), reduces tumor microvessel density and shows anti-proliferative activity in various solid tumors (4)(5)(6)(7).…”

Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2+/− Mice

“…A recent clinical trial of cabozantinib has shown significantly improved overall and progression-free survival of patients with advanced renal cell carcinoma [33]. Expression of VEGFR1 is increased and Akt is activated in TSC-associated renal tumors [19], [34]. Further investigations may, therefore, be worthwhile to compare CB-839 combined with cabozantinib with rapamycin or its analogs for TSC-associated renal lesions in Tsc2 +/− mice.…”

UPLC-MS based integrated plasma proteomic and metabolomic profiling of TSC-RAML and its relationship with everolimus treatment

“…Later, researchers found that mTOR1 plays a central role in the process of angiogenesis through multifactorial ways, including promoting VEGF-A expression by HIF-1α dependent and HIF-1α independent mechanism ( Dodd et al, 2015 ). Based on this hypothesis, additional experiments have suggested that a combination of rapalogs (Rapamycin and its analogs) and angiogenesis inhibitors, such as everolimus plus sorafenib, may significantly decrease the tumor size and improve the therapeutic efficacy by inhibiting mTORC1 and the mitogen-activated protein kinase (MAPK) pathway ( Yang et al, 2017 ), which is superior to the treatment with single rapalogs alone. Another study also found that angiogenesis inhibitors (sunitinib and bevacizumab) have therapeutic effects on TSC-related tumors, although they are not as effective as rapamycin ( Woodrum et al, 2010 ).…”