il-6 inhibition with medi5117 decreases the fraction of head and neck cancer stem cells and prevents tumor recurrence

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ID: 242898
2016
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Abstract
Head and neck squamous cell carcinomas (HNSCC) exhibit a small population of uniquely tumorigenic cancer stem cells (CSC) endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells (i.e. ALDHhighCD44high cells). Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117) using three low-passage patient-derived xenograft (PDX) models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors (P < .05). This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11). Low dose MEDI5117 (3 mg/kg) consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 (P < .001), PDX-SCC-M1 (P < .001), PDX-SCC-M11 (P = .04). Interestingly, high dose MEDI5117 (30 mg/kg) decreased the CSC fraction in the PDX-SCC-M11 model (P = .002), but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDHhighCD44high cells cultured in ultra-low attachment plates (P < .05), supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC.
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finkel2016neoplasia:il-6 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Kelsey A. Finkel;Kristy A. Warner;Samuel Kerk;Carol R. Bradford;Scott A. McLean;Mark E. Prince;Haihong Zhong;Elaine M. Hurt;Robert E. Hollingsworth;Max S. Wicha;David A. Tice;Jacques E. Nör
Journal ACS chemical neuroscience
Year 2016
DOI
10.1016/j.neo.2016.03.004
URL
http://www.sciencedirect.com/science/article/pii/S1476558616300021
Keywords
neoplasms Oncology including cancer and carcinogens tumors

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