IL-13 Receptors as Possible Therapeutic Targets in Diffuse Intrinsic Pontine Glioma

PLoS One. 2018 Apr 5;13(4):e0193565. doi: 10.1371/journal.pone.0193565. eCollection 2018.

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13α2 (IL-13Rα2) have demonstrated activity in this disease. To identify additional therapeutic markers for cell surface receptors, we performed exome sequencing (16 new samples, 22 previously published samples, total 38 with 26 matched normal DNA samples), RNA deep sequencing (17 new samples, 11 previously published samples, total 28 with 18 matched normal RNA samples), and immunohistochemistry (17 DIPG tissue samples) to examine the expression of the interleukin-4 (IL-4) signaling axis components (IL-4, interleukin 13 (IL-13), and their respective receptors IL-4Rα, IL-13Rα1, and IL-13Rα2). In addition, we correlated cytokine and receptor expression with expression of the oncogenes EGFR and c-MET. In DIPG tissues, transcript-level analysis found significant expression of IL-4, IL-13, and IL-13Rα1/2, with strong differential expression of IL-13Rα1/2 in tumor versus normal brain. At the protein level, immunohistochemical studies revealed high content of IL-4 and IL-13Rα1/2 but notably low expression of IL-13. Additionally, a strong positive correlation was observed between c-Met and IL-4Rα. The genomic and transcriptional landscape across all samples was also summarized. These data create a foundation for the design of potential new immunotherapies targeting IL-13 cell surface receptors in DIPG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Stem Neoplasms / drug therapy*
  • Brain Stem Neoplasms / genetics
  • ErbB Receptors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Glioma / drug therapy*
  • Glioma / genetics
  • Humans
  • Interleukin-4 / metabolism
  • Point Mutation
  • Receptors, Interleukin-13 / drug effects*
  • Receptors, Interleukin-13 / genetics
  • Receptors, Interleukin-4 / genetics
  • Receptors, Interleukin-4 / metabolism
  • Sequence Analysis, DNA

Substances

  • Receptors, Interleukin-13
  • Receptors, Interleukin-4
  • Interleukin-4
  • EGFR protein, human
  • ErbB Receptors

Grant support

Funded by Lyla Nsouli Foundation: http://www.lylansoulifoundation.org/ (CK). With Purpose: http://www.with-purpose.org/ (CK).