Our previous work was focused on "proof of concept" experiments to establish the clinical utility of pan PI-3 kinase inhibitors in preclinical models for glioma therapeutics and to evaluate the mechanisms for PTEN's regulation of glioma progression including elements of angiogenesis and downstream pharmacodynamic targets for PI-3 kinase action. Our previous experiments involved the study of a well-characterized pan PI-3 kinase inhibitor, LY294002 in glioma models. The LY294002 compound, for a number reasons (discussed below) is not a viable drug candidate for clinical development. In our competitive renewal we will focus on our current ongoing preclinical development of a novel small molecule inhibitor of PI-3 kinase co-developed in our laboratory (in collaboration with Semafore pharmaceuticals) for glioma therapeutics. This inhibitor is a vascular RGDS targeted prodrug derivative of LY294002 and is termed SF1126. Below we present our preliminary data which supports our proposal to further evaluate this targeted pan PI-3 kinase inhibitor in preclinical models for malignant glioma. Hypothesis: A pan PI-3 kinase inhibitor (SF1126) will attenuate the growth of malignant glial tumors in nude mice via its control over a number of important signaling pathways including the HIF1a-VEGF signaling axis. A pan PI-3 kinase inhibitor will display anti-glioma and antiangiogenic activity in vivo. Our goal is to perform formal PK-PD modeling of SF1126 as relates to PK and PD parameters, PTEN status of tumor and effects on angiogenesis and important downstream biomarkers. In the revised proposal, we will investigate the mechanism by which SF1126 controls HIF1a signaling in glioma cells a potential important component of its antiangiogenic activity. The primary goal our previous grant proposal, CA94233 was to: "determine the utility of pan PI-3 kinase inhibitor in preclinical models for glioma therapeutics". Herein, we present the development of a clinically viable pan PI-3 kinase inhibitor prodrug, SF1126 and we embark on a careful characterization of this agent in preclinical glioma models. The overarching goal is to prepare this agent for a Phase I clinical trial in glioma patients.

Public Health Relevance

The diagnosis of malignant glial tumors carries a dismal prognosis and there are no current therapies which can cure this type of brain tumor. Certain genetic changes are known to cause malignant brain tumors and these alterations have become targets for new drug development. In this proposal, we have developed one of the first PI-3 kinase inhibitors, termed SF1126 to enter human clinical trials. This proposal will provide useful information for the application of SF1126 to the treatment of malignant glial tumors in man and therefore may potentially improve survival of patients with this form of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Snyderwine, Elizabeth G
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University of California San Diego
Schools of Medicine
La Jolla
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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
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
Lee, Teresa; Di Paola, Domenic; Malina, Abba et al. (2014) Suppression of the DHX9 helicase induces premature senescence in human diploid fibroblasts in a p53-dependent manner. J Biol Chem 289:22798-814
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 R; Zulcic, Muamera et al. (2014) A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res 12:1520-31
Joshi, Shweta; Singh, Alok Ranjan; Zulcic, Muamera et al. (2014) A PKC-SHP1 signaling axis desensitizes Fcγ receptor signaling by reducing the tyrosine phosphorylation of CBL and regulates FcγR mediated phagocytosis. BMC Immunol 15:18
Joshi, Shweta; Singh, Alok R; Durden, Donald L (2014) MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem 289:22785-97
Muh, Carrie R; Joshi, Shweta; Singh, Alok R et al. (2014) PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1α suppression. J Neurooncol 116:89-97
Singh, Alok R; Peirce, Susan K; Joshi, Shweta et al. (2014) PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment. Exp Cell Res 327:78-90

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