mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC

Joseph D. Coppock, Paola Vermeer, Daniel W. Vermeer, Kimberly M. Lee, W. Keith Miskimins, William Spanos, John H. Lee

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)24228-24241
Number of pages14
JournalOncotarget
Volume7
Issue number17
DOIs
StatePublished - Apr 26 2016

Fingerprint

Squamous Cell Neoplasms
Head and Neck Neoplasms
Head
Sirolimus
Cisplatin
Radiotherapy
Neoplasm Metastasis
Cell Line
Therapeutics
Smegmamorpha
Protein Array Analysis
Adaptive Immunity
Standard of Care
Tumor Cell Line
Proteins
Lymph Nodes
Western Blotting
Lung
Population

Keywords

  • Head and neck oral cancer
  • Human papillomavirus
  • Metastasis
  • Rapamycin
  • mTOR

ASJC Scopus subject areas

  • Oncology

Cite this

Coppock, J. D., Vermeer, P., Vermeer, D. W., Lee, K. M., Miskimins, W. K., Spanos, W., & Lee, J. H. (2016). mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC. Oncotarget, 7(17), 24228-24241. https://doi.org/10.18632/oncotarget.8286

mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC. / Coppock, Joseph D.; Vermeer, Paola; Vermeer, Daniel W.; Lee, Kimberly M.; Miskimins, W. Keith; Spanos, William; Lee, John H.

In: Oncotarget, Vol. 7, No. 17, 26.04.2016, p. 24228-24241.

Research output: Contribution to journalArticle

Coppock, JD, Vermeer, P, Vermeer, DW, Lee, KM, Miskimins, WK, Spanos, W & Lee, JH 2016, 'mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC', Oncotarget, vol. 7, no. 17, pp. 24228-24241. https://doi.org/10.18632/oncotarget.8286
Coppock, Joseph D. ; Vermeer, Paola ; Vermeer, Daniel W. ; Lee, Kimberly M. ; Miskimins, W. Keith ; Spanos, William ; Lee, John H. / mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC. In: Oncotarget. 2016 ; Vol. 7, No. 17. pp. 24228-24241.
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