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Ref Type Journal Article
PMID (24162827)
Authors Muh CR, Joshi S, Singh AR, Kesari S, Durden DL, Makale MT
Title PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1α suppression.
Journal Vol Issue Date Pages Journal Short Title
Journal of neuro-oncology 116 1 2014 Jan 89-97 J Neurooncol
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN wild-type glioblastoma sensitive 2-Methoxyestradiol Preclinical Actionable In a preclinical study, 2-Methoxyestradiol (2ME2) inhibited tumor-induced angiogenesis and reduced tumor growth in PTEN reconstituted GBM cell lines and mouse models (PMID: 24162827). 24162827