Therapeutic targets in subependymoma

摘要

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-1 alpha, topoisomerase II-beta, p-STAT3, and nucleolin, but not EGFRvIII, EphA2, IL-13RA2, CMV, CTLA-4, FoxP3, PD-1, PD-L1, EGFR, PDGF-alpha, PDGF-beta, PDGFR-alpha, PDGFR-beta, PTEN, IGFBP2, PI3K, MDM4, IDH1, mTOR, or Jak2. A topoisomerase inhibitor (WP744, IC50 = 0.83 mu M) and a p-STAT3/HIF-1 alpha inhibitor (WP1066, IC50 = 3.15 mu M) 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. (C) 2014 Elsevier B.V. All rights reserved.