In Silico Models Accurately Predict In Vivo Response for IL6 Blockade in Head and Neck Cancer

Cancer Res. 2020 Apr 1;80(7):1451-1460. doi: 10.1158/0008-5472.CAN-19-1846. Epub 2020 Feb 10.

Abstract

Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies. SIGNIFICANCE: A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Dosage Calculations
  • Drug Synergism
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / metabolism
  • Mice
  • Models, Biological*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Signal Transduction / drug effects
  • Squamous Cell Carcinoma of Head and Neck / drug therapy*
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Time Factors
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • IL6 protein, human
  • Interleukin-6
  • tocilizumab
  • Cisplatin