title: mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.
abstract: Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0-30% improved to 78-100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis.
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Coppock
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
authors.forename: Paola D
authors.initials: PD
authors.lastname: Vermeer
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
authors.forename: W Keith
authors.initials: WK
authors.lastname: Miskimins
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.|Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, SD 57105, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Spanos
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.|Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, SD 57105, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus
keywords: head and neck oral cancer; human papillomavirus; mTOR; metastasis; rapamycin