mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC
Metrics: PDF 1606 views | HTML 1673 views | ?
Joseph D. Coppock1, Paola D. Vermeer1, Daniel W. Vermeer1, Kimberly M. Lee1, W. Keith Miskimins1, William C. Spanos1,2, John H. Lee1,2
1Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA
2Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, SD 57105, USA
John H. Lee, e-mail: email@example.com
Keywords: head and neck oral cancer, human papillomavirus, metastasis, rapamycin, mTOR
Received: October 19, 2015 Accepted: March 06, 2016 Published: March 23, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.