BACKGROUND: Rapamycin is an mTOR inhibitor with preclinical efficacy in squamous cell carcinoma of the head and neck (SCCHN). However, mTOR inhibitors also increase Akt activity in SCCHN cell lines, which would promote survival and oncogenesis. Enzastaurin is an AGC kinase inhibitor with nanomolar inhibitory concentrations for Akt and protein kinase C (PKC). Moreover, Akt and PKC inhibitors have demonstrated efficacy in SCCHN. METHODS: We hypothesized that the combination of rapamycin and enzastaurin would be more effective than either agent alone. RESULTS: Rapamycin and enzastaurin generally inhibited putative targets in SCCHN cell lines in culture. In mice xenografted with CAL27 cells, rapamycin and enzastaurin produced growth delay. In contrast, the combination of rapamycin and enzastaurin caused regression of CAL27 tumors with evidence of inhibition of putative targets, survival, angiogenesis and proliferation. CONCLUSION: These data demonstrate that the combination of rapamycin and enzastaurin disrupts critical oncogenic pathways in SCCHN and has efficacy in preclinical models.
BACKGROUND:Rapamycin is an mTOR inhibitor with preclinical efficacy in squamous cell carcinoma of the head and neck (SCCHN). However, mTOR inhibitors also increase Akt activity in SCCHN cell lines, which would promote survival and oncogenesis. Enzastaurin is an AGC kinase inhibitor with nanomolar inhibitory concentrations for Akt and protein kinase C (PKC). Moreover, Akt and PKC inhibitors have demonstrated efficacy in SCCHN. METHODS: We hypothesized that the combination of rapamycin and enzastaurin would be more effective than either agent alone. RESULTS:Rapamycin and enzastaurin generally inhibited putative targets in SCCHN cell lines in culture. In mice xenografted with CAL27 cells, rapamycin and enzastaurin produced growth delay. In contrast, the combination of rapamycin and enzastaurin caused regression of CAL27 tumors with evidence of inhibition of putative targets, survival, angiogenesis and proliferation. CONCLUSION: These data demonstrate that the combination of rapamycin and enzastaurin disrupts critical oncogenic pathways in SCCHN and has efficacy in preclinical models.
Authors: Gregory N Gan; Justin Eagles; Stephen B Keysar; Guoliang Wang; Magdalena J Glogowska; Cem Altunbas; Ryan T Anderson; Phuong N Le; J Jason Morton; Barbara Frederick; David Raben; Xiao-Jing Wang; Antonio Jimeno Journal: Cancer Res Date: 2014-10-08 Impact factor: 12.701
Authors: Chih-Pin Chuu; Hui-Ping Lin; Mark F Ciaccio; John M Kokontis; Ronald J Hause; Richard A Hiipakka; Shutsung Liao; Richard Baker Jones Journal: Cancer Prev Res (Phila) Date: 2012-05
Authors: Natalie R Young; Christian Soneru; Jing Liu; Tatyana A Grushko; Ashley Hardeman; Olufunmilayo I Olopade; Anke Baum; Flavio Solca; Ezra E W Cohen Journal: Target Oncol Date: 2015-01-06 Impact factor: 4.493