mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo.
BACKGROUND
Gastric cancer is a highly chemoresistant tumor. Previous studies suggest that cancer cells can be sensitized to standard chemotherapy, and especially alkylating agents, by inhibition of mammalian target of rapamycin (mTOR) signaling. The work presented here shows that the mTOR inhibitor everolimus, in combination with cyclophosphamide, exhibits synergistic antitumor activity in gastric cancer xenografts.


METHODS
Treatment with everolimus at the minimal effective dose was studied in combination with cyclophosphamide at maximum tolerated dose in a human gastric cancer severe combined immunodeficient (SCID) mouse xenograft model. Besides tumor size, biomarker expression for proliferation (Ki-67), hypoxia (HIF-12alpha), apoptosis (activated caspase 3), angiogenesis (microvascular density, MVD) and levels of circulating endothelial progenitors (CEPs) were assessed.


RESULTS
Everolimus single agent treatment significantly inhibited tumor growth relative to control and cyclophosphamide treatment (T/C 19%, p<0.01). This antitumor activity was linked to a significant decrease in tumor cell proliferation (p<0.01) and a trend towards lower tumor MVD, HIF-1alpha expression and levels of CEPs. Notably, the combination of everolimus with cyclophosphamide resulted in synergistic anti-tumor activity (T/C 9%, p<0.01). This antitumor activity coincided with a statistically significant decrease in MVD (p<0.01). Whereas treatment with everolimus was well tolerated, cyclophosphamide at maximum tolerated dose (MTD) showed significant toxicity both as monotherapy and in combination with everolimus.


CONCLUSIONS
The antiangiogenic activity of everolimus combined with a high dose of cyclophosphamide shows synergistic antitumor activity against gastric cancer in vivo. In potential future clinical trials, the toxicity of cyclophosphamide in combination regimens with everolimus deserves careful evaluation.
Cejka
Daniel
D
Section of Experimental Oncology/Molecular Pharmacology, Department of Clinical Pharmacology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Preusser
Matthias
M
Fuereder
Thorsten
T
Sieghart
Wolfgang
W
Werzowa
Johannes
J
Strommer
Sabine
S
Wacheck
Volker
V
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D047428:Protein Kinase Inhibitors; D003520:Cyclophosphamide; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus