IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma

Noah E. Berlow, Matthew N. Svalina, Michael J. Quist, Teagan P. Settelmeyer, Viktor Zherebitskiy, Mari Kogiso, Lin Qi, Yuchen Du, Cynthia E. Hawkins, Esther Hulleman, Xiao Nan Li, Sakir H. Gultekin, Charles Keller

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0193565
JournalPloS one
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2018

Fingerprint

Interleukin-13 Receptors
Interleukin-13
Glioma
Interleukin-4
Interleukin-2
therapeutics
receptors
Cell Surface Receptors
interleukin-4
Epidermal Growth Factor Receptor
Immunotherapy
Brain
Interleukin Receptors
RNA
Tissue
Exome
RNA Sequence Analysis
High-Throughput Nucleotide Sequencing
sampling
Cytokine Receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Berlow, N. E., Svalina, M. N., Quist, M. J., Settelmeyer, T. P., Zherebitskiy, V., Kogiso, M., ... Keller, C. (2018). IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma. PloS one, 13(4), [e0193565]. https://doi.org/10.1371/journal.pone.0193565
Berlow, Noah E. ; Svalina, Matthew N. ; Quist, Michael J. ; Settelmeyer, Teagan P. ; Zherebitskiy, Viktor ; Kogiso, Mari ; Qi, Lin ; Du, Yuchen ; Hawkins, Cynthia E. ; Hulleman, Esther ; Li, Xiao Nan ; Gultekin, Sakir H. ; Keller, Charles. / IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma. In: PloS one. 2018 ; Vol. 13, No. 4.
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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.",
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Berlow, NE, Svalina, MN, Quist, MJ, Settelmeyer, TP, Zherebitskiy, V, Kogiso, M, Qi, L, Du, Y, Hawkins, CE, Hulleman, E, Li, XN, Gultekin, SH & Keller, C 2018, 'IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma', PloS one, vol. 13, no. 4, e0193565. https://doi.org/10.1371/journal.pone.0193565

IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma. / Berlow, Noah E.; Svalina, Matthew N.; Quist, Michael J.; Settelmeyer, Teagan P.; Zherebitskiy, Viktor; Kogiso, Mari; Qi, Lin; Du, Yuchen; Hawkins, Cynthia E.; Hulleman, Esther; Li, Xiao Nan; Gultekin, Sakir H.; Keller, Charles.

In: PloS one, Vol. 13, No. 4, e0193565, 01.04.2018.

Research output: Contribution to journalArticle

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T1 - IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma

AU - Berlow, Noah E.

AU - Svalina, Matthew N.

AU - Quist, Michael J.

AU - Settelmeyer, Teagan P.

AU - Zherebitskiy, Viktor

AU - Kogiso, Mari

AU - Qi, Lin

AU - Du, Yuchen

AU - Hawkins, Cynthia E.

AU - Hulleman, Esther

AU - Li, Xiao Nan

AU - Gultekin, Sakir H.

AU - Keller, Charles

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N2 - 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.

AB - 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.

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Berlow NE, Svalina MN, Quist MJ, Settelmeyer TP, Zherebitskiy V, Kogiso M et al. IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma. PloS one. 2018 Apr 1;13(4). e0193565. https://doi.org/10.1371/journal.pone.0193565