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

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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.

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Acknowledgments

We thank Dr. H.K Shu for providing the EGFRvIII transduced LN229 cell line. This work was supported in part by a grant from EntreMed, Inc. 9640 Medical Center Drive, Rockville, MD 20850 and NIH grants CA94233 and HL091365 to Dr. Donald L. Durden, and a grant from the Musella Foundation and Heroes of Hope Coalition to Dr. Carrie Muh.

Conflict of interest

D. Durden discloses financial conflict of interest related to the development of SF1126. This aspect has been reviewed by the UCSD committee on conflict of interest.

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Authors and Affiliations

  1. Department of Neurosurgery and Pediatrics, Duke University Medical Center, Durham, NC, USA

    Carrie R. Muh

  2. Department of Pediatrics, Moores Cancer Center, University of California, San Diego, RM 5305, 3855 Health Sciences Drive, #0819, La Jolla, CA, 92093-0819, USA

    Shweta Joshi, Alok R. Singh & Donald L. Durden

  3. Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

    Santosh Kesari & Milan T. Makale

  4. Department of Pediatrics, Rady Children’s Hospital, University of California, San Diego, San Diego, CA, USA

    Donald L. Durden

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  1. Carrie R. Muh
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  2. Shweta Joshi
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Correspondence to Donald L. Durden.

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Muh, C.R., Joshi, S., Singh, A.R. et al. PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1α suppression. J Neurooncol 116, 89–97 (2014). https://doi.org/10.1007/s11060-013-1283-3

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  • DOI: https://doi.org/10.1007/s11060-013-1283-3

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