| Title |
PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1α suppression
|
|---|---|
| Published in |
Journal of Neuro-Oncology, October 2013
|
| DOI | 10.1007/s11060-013-1283-3 |
| Pubmed ID | |
| Authors |
Carrie R. Muh, Shweta Joshi, Alok R. Singh, Santosh Kesari, Donald L. Durden, Milan T. Makale |
| 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. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 31 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 31 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 10 | 32% |
| Student > Ph. D. Student | 6 | 19% |
| Student > Bachelor | 5 | 16% |
| Other | 2 | 6% |
| Student > Master | 2 | 6% |
| Other | 1 | 3% |
| Unknown | 5 | 16% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 6 | 19% |
| Medicine and Dentistry | 5 | 16% |
| Biochemistry, Genetics and Molecular Biology | 4 | 13% |
| Neuroscience | 3 | 10% |
| Immunology and Microbiology | 1 | 3% |
| Other | 1 | 3% |
| Unknown | 11 | 35% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 August 2014.
All research outputs
#20,234,388
of 22,760,687 outputs
Outputs from Journal of Neuro-Oncology
#2,566
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#185,261
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Outputs of similar age from Journal of Neuro-Oncology
#33
of 46 outputs
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