Asunto(s)
Carcinoma de Células Escamosas , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Virus del Papiloma Humano , ADN Tumoral Circulante/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Papillomaviridae/genética , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/patología , Infecciones por Papillomavirus/complicacionesRESUMEN
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.