TY - JOUR
T1 - Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia
AU - Govindarajan, Baskaran
AU - Willoughby, Laura
AU - Band, Hamid
AU - Curatolo, Adam S.
AU - Veledar, Emir
AU - Chen, Suephy
AU - Bonner, Michael Y.
AU - Abel, Martin Garrido
AU - Moses, Marsha A.
AU - Arbiser, Jack L.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012
Y1 - 2012
N2 - Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.
AB - Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.
UR - http://www.scopus.com/inward/record.url?scp=84866057854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866057854&partnerID=8YFLogxK
U2 - 10.1186/2045-824X-4-11
DO - 10.1186/2045-824X-4-11
M3 - Article
C2 - 22765013
AN - SCOPUS:84866057854
VL - 4
JO - Vascular Cell
JF - Vascular Cell
SN - 2045-824X
M1 - 11
ER -