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wp1122 e 1222

Abstracts vi86 NEURO-ONCOLOGY • NOVEMBER 2018 Glioblastoma is one of the most deadly cancers and limited to only a few therapeutic options that are available in clinical settings, mainly due to the resistance to many chemotherapies. MicroRNAs are increasingly implicated in the tumor survival from chemotherapies, which may lead to a better therapeutic option by overcoming the resistance. Here, we found that miR138 is significantly downregulated in human glioblastoma patient tissues compared to normal brain tissues. MiR-138 has been known to play as a tumor suppressor in many types of cancer, which may imply that miR-138 can benefit in the development of anti-glioblastoma therapy. Global proteomic analysis revealed that ectopic expression of miR-138 in patient derived glioblastoma primary cells suppressed FAK pathway, which has been known to be highly activated in many cancers including glioblastoma. FAK inactivation by miR-138 resulted inhibition of glioblastoma cell proliferation in vitro and improved tumor free survival in vivo. We also found that miR138 induced FAK inhibition sensitizes glioblastoma cells to tyrosine kinase inhibitors, such as Imatinib. The studies are indicative of the clinical benefit of miR-138 based therapy of primary and even recurrent glioblastoma. EXTH-06. CD38-TARGETED THERAPY IN GLIOBLASTOMA Sonikpreet Aulakh, Alak Manna, Paula Schiapparelli, Sikander Ailawadhi, Aneel Paulus, Steven Rosenfeld, Alfredo Quinones-Hinojosa and Asher Chanan-Khan; Mayo Clinic Jacksonville, Jacksonville, FL, USA BACKGROUND: Glioblastoma (GBM) remains a malignancy with a dismal prognosis in spite of current optimal management, including maximal resection, radiation therapy, and alkylating chemotherapy. Relapse is inevitable with the paucity of further effective therapies. The development of novel targeted therapeutics is of prime importance. One such target is CD38, a transmembrane glycoprotein, partakes in receptor-mediated adhesion and cell signaling. It is expressed on GBM microglia/macrophages microenvironment. In vivo studies have shown decreased tumor growth and increased survival in CD38 genetic knockout mice, as well as with the use of K-rhein. Daratumumab (DARA) is an FDA-approved IgG1 kappa human monoclonal antibody, with the ability to penetrate blood brain barrier, that upon binding to CD38-bearing tumor cells lead to apoptosis, immune-mediated cell death and downregulation of the immunosuppressive environment. Hence, we wished to see if DARA could enhance efficacy of GBM directed therapies. METHODS: We used flow cytometric analysis to identify CD38 expression on human GBM cells. MTS viability assay is used to detect IC50 of DARA. In addition, Annexin V/PI dual staining is used to detect apoptosis. Further, antibody-dependent cell mediated cytotoxicity (ADCC) and complement mediated cytotoxicity (CDC) assays are used. Additionally, evaluated the effect of DARA on cytotoxicT-cell proliferation. RESULTS: Our in vitro data shows that 9% of human GBM cells express CD38 with 250 MFI. IC50 of DARA+DMSO was 150µg/ml vs 75µg/ ml with DARA+ temozolomide (TMZ). MTS assay revealed apoptosis after treatment with DARA+TMZ (44.25  ±  1.05%)> DARA (36.33  ±  0.87%) >TMZ (26.59 ± 0.93%, p<0.05) in comparison with control(C, 5.359%). % specific lysis via ADCC assay: TMZ+DARA (56.74 ± 2.84%) > DARA (35.30 ± 4.12%) > TMZ (20.57 ± 4.89%), vs C (4.30 ± 1.74%). % specific lysis via CDC with DARA (70.28 ± 9.28%) > TMZ (44.49 ± 0.72%, p<0.05), vs C (7.07  ±  0.72). Cytotoxic CD8+ T-cell proliferation was induced with DARA (59.29%) >TMZ (40.47%) > TMZ+DARA (45.82%), vs C (1.43%). CONCLUSIONS: Hence, CD38 is a potential target in GBM that if targeted with DARA +/- TMZ will generate direct anti-GBM effect as well as modulate the tumor microenvironment. EXTH-07. DESIGN AND EVALUATION OF WP1122, AN INHIBITOR OF GLYCOLYSIS WITH INCREASED CNS UPTAKE. Waldemar Priebe, Rafal Zielinski, Izabela Fokt, Edward Felix, Venugopal Radjendirane, Jayakumar Arumugam, Matthew Tai Khuong, Maciej Krasinski and Stanislaw Skora; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Glioblastoma (GBM), an aggressive primary brain tumor, relies on anaerobic glycolysis to produce energy. A  known inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG) has been clinically tested but its poor drug-like characteristics limited its practical application for cancer treatment. To overcome this problem, we have performed latentiation of 2-DG. Chemical modification of biologically active 2-DG led to the formation of prodrugs with improved pharmacokinetic and pharmacodynamic properties and subsequently to selection of the lead compound WP1122 (3,6-di-O-acetyl2-deoxy-D-glucose). Unlike 2-DG, its prodrug WP1222 enters cells and cross blood-brain barrier by passive diffusion rather than by specific glucose transporter, then undergoes deacetylation by esterases and is trapped inside the cell after phosphorylation at C-6 hydroxyl group.  6-phospho-2-deoxy glucose acts as a competitive inhibitor of hexokinase (HK) blocking phosphorylation of D-glucose and subsequently inhibiting glycolytic pathway. Our in vitro experiments confirmed inhibition of glycolysis in U87 cells and high sensitivity of broad spectrum of cancer cells to WP1122 both in hypoxic and normoxic conditions (IC50 range from 1–10  mM). In vivo studies showed that WP1122 is well tolerated by animals even with prolonged exposure and extend survival of mice in orthotopic U87 GBM model. Initial pharmacokinetic experiments demonstrated rapid uptake of WP1122 after oral administration allowing to achieve two orders of magnitude higher maximum concentration of 2-DG in plasma, compared to animals treated with an equal molar dose of pure 2-DG. We also observed significantly higher levels of 2-DG in brains of mice treated with WP1122 than in mice receiving equal dose of 2-DG. In summary, WP1122 is a biologically effective prodrug of 2-DG with a good toxicity profile and promising pharmacokinetic characteristics that warrants detail preclinical and clinical development as a potential therapeutic agent for glioblastomas and other highly glycolytic tumors. EXTH-08. MESENCHYMAL GLIOBLASTOMA CONSTITUTES A MAJOR ceRNA SIGNATURE IN THE TGF-PATHWAY Qixue Wang1, Yunfei Wang2, Chuan Fang3, Yanli Tan4 and Chunsheng Kang2; 1Tianjin Medical University, Tianjin, China, 2Tianjin Medical University General Hospital, Tianjin, China, 3Department of Neurosurgery, Hebei University Affiliated Hospital, Baoding, Hebei, China, 4Department of Pathology, Medical College of Hebei University, Baoding, Hebei, China ceRNA networks play important roles in post-transcriptional regulation. Their dysregulation is common in cancer. However, ceRNA signatures are barely examined for mesenchymal glioblastoma characteristic of invasive and aggressive phenotypes. Here, we investigated the mRNAs in ceRNA networks (micNET) of glioblastoma by constructing a GBM ceRNA network, followed by being integrated with STRING protein interaction network. We report that six micNETs (TGFBR2, RUNX1, PPARG, ACSL1, GIT2 and RAP1B) signify mesenchymal GBM across multiple datasets. Patients with highly expressed micNET markers have poor response to TMZ chemotherapy. Mechanistically, the ceRNA interaction were identified between micNETs and miR181s family members. The inhibitor of TGFBR2, LY2109761, demonstrated tumor-suppressive effect on both primary cultured cell and PDX intracranial model. Thereby, the micNETs provide a promising translational significance in diagnosis of mesenchymal GBM as well as novel therapeutic targets. In conclusion, our study revealed that the ceRNA signature of mesenchymal glioblastoma was enriched in the TGF-β pathway and characterized this subtype in the mRNA-miRNA dimension. We identified that key micNETs signatures could be used to diagnose mesenchymal GBM and discovered that the TGF-β pathway is a potential therapeutic target for mesenchymal glioblastoma. EXTH-09. DIANHYDROGALACTITOL (VAL-083) HAS THE POTENTIAL TO OVERCOME MAJOR CHALLENGES IN THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) Anne Steino1, BeiBei Zhai2, Xiaodong Yang3, Cassie Kline3, Jeffrey Bacha1, Dennis Brown4, Mads Daugaard2 and Sabine Mueller5; 1DelMar Pharmaceuticals, Inc, Vancouver, BC, Canada, 2University of British Columbia, Vancouver, BC, Canada, 3University of California, San Francisco, San Francisco, CA, USA, 4DelMar Pharmaceuticals, Inc, San Francisco, CA, USA, 5Department of Neurology, University of California, San Francisco, San Francisco, CA, USA OBJECTIVE: VAL-083 is a structurally unique bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Herein we assess the activity of VAL-083 as single agent as well as in combination regimens including Wee1 Kinase inhibitor AZD1775 and radiation therapy in patient derived model systems of DIPG.  METHODS: DIPG derived cell lines SF8628 and NEM157 (H3.3K27) as well as SF10693 (H3.1K27M) and pediatric glioblastoma cell lines SF188 (H3.3K27 wildtype) were treated with increasing concentrations of single agent VAL-083 as well as in combination with AZD1775 and radiation therapy. To determine potential synergistic activity, we applied the Chou-Talalay method, which allows the quantitative determination of drug interactions by calculating a combination index (CI). In vivo activity of VAL-083 as single agent as well as in combination with AZD1775 was assessed in an orthotopic engraftment model of pediatric DIPG (SF8628). RESULTS: The IC50 of VAL-083 ranged from 2.1uM to 19.7uM. The combination of VAL-083 and AZD1775 showed synergistic activity in all tested cell lines with CI ranging from 0.405 to 2.066 with < 1 indicating synergy whereas VAL-083 combined with radiation therapy led to only additive effects. Initial in vivo study showed that combined treatment with VAL083 and AZD1775 conferred greater survival benefit to mice with engrafted DIPG tumors compared to control as well as single agent treatment. Day 49 after therapy initiation shows: Control: 2/10; AZD1775: 4/10; VAL083 7/10 and VAL-083+AZD1775: 11/11 mice alive. CONCLUSION: Our present study highlights that the combination of VAL-083 and AZD1775 might be a promising new therapeutic strategy for children with DIPG. Ongoing studies will continue to assess the in vivo activity as well explore the underlying mechanism of action of the combination strategy. Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_6/vi86/5154181 by guest on 18 May 2020