Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001.
Johansson
Gunnar
G
Division of Experimental Hematology, University of Cincinnati, Cincinnati, OH, USA.
Mahller
Yonatan Y
YY
Collins
Margaret H
MH
Kim
Mi-Ok
MO
Nobukuni
Takahiro
T
Perentesis
John
J
Cripe
Timothy P
TP
Lane
Heidi A
HA
Kozma
Sara C
SC
Thomas
George
G
Ratner
Nancy
N
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016923:Cell Death; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D000069347:Erlotinib Hydrochloride; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011799:Quinazolines; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D020123:Sirolimus