Targeting of glioma stem-like cells with a parthenolide derivative ACT001 through inhibition of AEBP1/PI3K/AKT signaling

Glioblastoma (GBM) is the most lethal primary brain tumor in adults with a median survival of around 15 months. A potential treatment strategy involves targeting glioma stem-like cells (GSCs) that are able to initiate, maintain, and repopulate mass. Here, we identify ACT001, parthenolide derivative, GSCs through regulation adipocyte enhancer binding protein 1 (AEBP1) signaling. Methods: The effects ACT001 on cell normal human astrocytes (NHA) patient-derived were evaluated. RNA-Seq performed detect differentially expressed genes. efficacy as single agent or combination SHP-2 inhibitor SHP099 was assessed using GSC orthotopic xenograft model. Results: exhibit high response compared astrocytes. AEBP1 putative target by analysis, which expression associates prognosis GBM patients. Knockdown inhibits proliferation sphere formation. Treatment PI3K depletion would impair AKT phosphorylation proliferation, whereas constitutive activation rescues depletion-inhibited proliferation. Moreover, blocks TGF-?-activated AEBP1/AKT signaling GSCs. exhibits antitumor activity either SHP099, provides significant benefits for xenograft-bearing animals. Conclusions: Our data demonstrate new druggable therapeutic option improving clinical SHP099.