Therapeutic targets in subependymoma.

Abstract

Subependymomas are usually treated with surgical resection; however, no standard, defined alternative medical therapy is recommended for patients who are not surgical candidates, owing to a paucity of molecular, immunological, and genetic characterization. To address this, an ex vivo functional analysis of the immune microenvironment in subependymoma was conducted, a subependymoma cytokine/chemokine microarray was constructed for the evaluation of operational immune and molecular pathways, and a subependymoma cell line was derived and used to test a variety of cytotoxic agents that target operational pathways identified in subependymoma. We found that immune effectors are detectable within the microenvironment of subependymoma; however, marked immune suppression is not observed. The subependymoma tissue microarrays demonstrated tumor expression of p53, MDM2, HIF-1α, topoisomerase II-β, p-STAT3, and nucleolin, but not EGFRvIII, EphA2, IL-13RA2, CMV, CTLA-4, FoxP3, PD-1, PD-L1, EGFR, PDGF-α, PDGF-β, PDGFR-α, PDGFR-β, PTEN, IGFBP2, PI3K, MDM4, IDH1, mTOR, or Jak2. A topoisomerase inhibitor (WP744, IC50=0.83 μM) and a p-STAT3/HIF-1α inhibitor (WP1066, IC50=3.15 μM) demonstrated a growth inhibition of the subependymoma cell proliferation. Cumulatively, these data suggest that those agents that interfere with oncogenes operational in subependymoma may have clinical impact.

• Authors: Ling-Yuan Kong, Jun Wei, Ali S Haider, Brandon D Liebelt, Xiaoyang Ling, Charles A Conrad, Gregory N Fuller, Nicholas B Levine, Waldemar Priebe, Raymond Sawaya, Amy B Heimberger
• Journal: Journal of neuroimmunology (J Neuroimmunol) Vol. 277 Issue 1-2 Pg. 168-75 (Dec 15 2014) ISSN: 1872-8421 [Electronic] Netherlands
• PMID: 25465288 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cytokines
• Neoplasm Proteins
• Pyridines
• Tyrphostins
• WP1066

Topics

• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Brain Neoplasms (embryology, metabolism, pathology)
• Cell Line, Tumor (drug effects)
• Cell Proliferation (drug effects)
• Colony-Forming Units Assay
• Cytokines (genetics, metabolism)
• Cytotoxicity Tests, Immunologic
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma, Subependymal (immunology, metabolism, pathology)
• Humans
• Neoplasm Proteins (genetics, metabolism)
• Neoplastic Stem Cells (drug effects, immunology, metabolism)
• Pyridines (chemistry, pharmacology)
• Signal Transduction (drug effects, physiology)
• T-Lymphocytes (drug effects, immunology)
• Tissue Array Analysis
• Tyrphostins (chemistry, pharmacology)