Research

Vascular Cell

, 4:11

Open Access This content is freely available online to anyone, anywhere at any time.

Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

  • Baskaran GovindarajanAffiliated withDepartment of Dermatology, Emory University School of Medicine, Winship Cancer Institute and Atlanta Veterans Administration Hospital, WMB 5309
  • , Laura WilloughbyAffiliated withEppley Institute for Research in Cancer and Allied Diseases, UNMC-Eppley Cancer Center, University of Nebraska Medical Center
  • , Hamid BandAffiliated withEppley Institute for Research in Cancer and Allied Diseases, UNMC-Eppley Cancer Center, University of Nebraska Medical Center
  • , Adam S CuratoloAffiliated withVascular Biology Program, Children’s Hospital Boston, Department of Surgery, Children’s Hospital Boston and Harvard Medical School Karp Family Research Laboratories
  • , Emir VeledarAffiliated withDepartment of Cardiology, Emory University School of Medicine
  • , Suephy ChenAffiliated withDepartment of Dermatology, Emory University School of Medicine, Winship Cancer Institute and Atlanta Veterans Administration Hospital, WMB 5309
  • , Michael Y BonnerAffiliated withDepartment of Dermatology, Emory University School of Medicine, Winship Cancer Institute and Atlanta Veterans Administration Hospital, WMB 5309
  • , Martin-Garrido AbelAffiliated withDepartment of Cardiology, Emory University School of Medicine
  • , Marsha A MosesAffiliated withVascular Biology Program, Children’s Hospital Boston, Department of Surgery, Children’s Hospital Boston and Harvard Medical School Karp Family Research Laboratories
    • , Jack L ArbiserAffiliated withDepartment of Dermatology, Emory University School of Medicine, Winship Cancer Institute and Atlanta Veterans Administration Hospital, WMB 5309 Email author 

Abstract

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.