title: Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition.
abstract: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic) target of rapamycin (mTOR) inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT) to attenuate tumor lactate production, thus enhancing CRT-induced immune-mediated clearance of this antigenic tumor type. A C57Bl/6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays. Clonogenic assays and a preclinical mouse model were used to assess rapamycin as a concurrent agent to CRT. The potential of rapamycin to enhance immune response through lactate attenuation was assessed using quantitative tumor lactate bioluminescence and assessment of cell-mediated immunity using E6/E7-vaccinated mouse splenocytes. Rapamycin alone inhibited mTOR signaling of all cancer cell lines tested in vitro and in vivo. Furthermore, rapamycin administered alone significantly prolonged survival in vivo but did not result in any long-term cures. Given concurrently, CRT/rapamycin significantly enhanced direct cell killing in clonogenic assays and prolonged survival in immunocompromised mice. However, in immunocompetent mice, concurrent CRT/rapamycin increased long-term cures by 21%. Preliminary findings suggest that improved survival involves increased cell killing and enhanced immune-mediated clearance in part due to decreased lactate production. The results may provide rationale for the clinical evaluation of mTOR inhibitors concurrent with standard-of-care CRT for treatment of HPV-positive HNSCC.
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Coppock
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Wieking
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: W Keith
authors.initials: WK
authors.lastname: Miskimins
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy / Q000821:virology*; D052162:Human papillomavirus 16 / Q000472:pathogenicity; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007773:Lactates / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D030361:Papillomavirus Infections / Q000150:complications*; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007773:Lactates; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus