Currently the treatment outcome of malignant glial brain tumors in adult and pediatric patients is poor. Mutations of the tumor suppressor, PTEN, a dual specificity protein phosphatase which dephosphorylates acidic peptides and inositol phospholipids, accompany progression of pediatric and adult brain tumors from benign to the most malignant forms. Brain tumor progression, particularly in aggressive and malignant brain tumors, is associated with augmented proliferation and the induction of angiogenesis. Our preliminary data support the hypothesis that PTEN regulates brain tumor progression by modulating the angiogenic response. U87MG glioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the introduction of wild type PTEN resulted in decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these cells. These changes correlated with diminished phosphorylation of AKT within the PTEN-reconstituted tumor and diminished angiogenic activity, as determined by microvessel density and augmented thrombospondin 1 expression. These effects were not observed in tumors reconstituted with the G129E mutant form of PTEN in which lipid phosphatase activity is ablated. These data support our hypothesis and indicate that, in addition to the reported effects of PTEN on proliferation and cell survival, loss of PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals. Based on our preliminary data we propose to evaluate the role of PTEN and PI-3 kinase in brain tumor progression as it relates to the angiogenic response and to determine if PI-3 kinase inhibitors can block brain tumor growth, the angiogenic response and promote survival. These experiments will provide important preclinical data to support the development of PI-3 kinase inhibitors for the treatment of malignant glial tumors associated with a deregulated PI-3 kinase/AKT signaling axis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-PTHC (01))
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Macleod, Carol L
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Emory University
Schools of Medicine
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Erdreich-Epstein, Anat; Singh, Alok R; Joshi, Shweta et al. (2017) Association of high microvessel ?v?3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. Oncotarget 8:52193-52210
Andrews, Forest H; Singh, Alok R; Joshi, Shweta et al. (2017) Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis. Proc Natl Acad Sci U S A 114:E1072-E1080
Singh, Alok R; Joshi, Shweta; Zulcic, Muamera et al. (2016) PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma. PLoS One 11:e0150836
Singh, Alok R; Joshi, Shweta; Burgoyne, Adam M et al. (2016) Single Agent and Synergistic Activity of the ""First-in-Class"" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma. Mol Cancer Ther 15:2553-2562
Bhat, Vikas; Olmer, Merissa; Joshi, Shweta et al. (2015) Vascular remodeling underlies rebleeding in hemophilic arthropathy. Am J Hematol 90:1027-35
Joshi, Shweta; Singh, Alok R; Durden, Donald L (2015) Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma. Cancer Chemother Pharmacol 75:595-608
Joshi, Shweta; Singh, Alok R; Zulcic, Muamera et al. (2014) Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PLoS One 9:e95893
Joshi, Shweta; Singh, Alok Ranjan; Zulcic, Muamera et al. (2014) A PKC-SHP1 signaling axis desensitizes Fc? receptor signaling by reducing the tyrosine phosphorylation of CBL and regulates Fc?R mediated phagocytosis. BMC Immunol 15:18
Muh, Carrie R; Joshi, Shweta; Singh, Alok R et al. (2014) PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1? suppression. J Neurooncol 116:89-97
Joshi, Shweta; Singh, Alok R; Zulcic, Muamera et al. (2014) A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1? and HIF2? stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res 12:1520-31

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