PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: Role of HIF1α suppression

Carrie R. Muh, Shweta Joshi, Alok R. Singh, Santosh Kesari, Donald L. Durden, Milan T. Makale

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Glioblastoma (GBM) is the most common brain cancer and is highly lethal in both adults and children. 2-methoxyestradiol (2ME2) is a microtubule inhibitor that potently inhibits HIF1α, GBM angiogenesis and tumor growth in preclinical models. In patients, 2ME2 exhibits low toxicity and promising but inconsistent efficacy. Given its preclinical potency and its tolerability in patients, we sought to determine whether 2ME2 therapy could be enhanced by addressing resistance via combination therapy, and with biomarkers to identify responsive glioma subgroups. We demonstrate that the PTEN-PI3K axis regulates HIF1α in glioma models. We utilized isogenic-pairs of glioma cell lines, deficient in PTEN or stably reconstituted with PTEN, to determine the role of PTEN in 2ME2 sensitivity in vitro and in vivo. Chou-Talalay synergy studies reveal significant synergy when a pan-PI3K inhibitor is combined with 2ME2. This synergistic activity was correlated with a synergistic suppression of HIF1α accumulation under hypoxic conditions in glioma models. In vivo, 2ME2 markedly inhibited tumor-induced angiogenesis and significantly reduced tumor growth only in a PTEN reconstituted GBM models in both subcutaneous and orthotopic intracranial mouse models. Collectively, these results: (1) suggest that PTEN status predicts sensitivity to 2ME2 and (2) justify exploration of 2ME2 combined with pan-PI3K inhibitors for the treatment of this intractable brain cancer.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalJournal of Neuro-Oncology
Volume116
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • 2ME2
  • Angiogenesis
  • Glioblastoma multiforme
  • HIF1α
  • PI3K
  • PTEN

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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