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Virginiabrainrx: a Symposium on Drug Discovery for the Brain

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Virginiabrainrx: a Symposium on Drug Discovery for the Brain Virginia Drug Discovery Consortium VirginiaBrainRx: A Symposium on Drug Discovery for the Brain Poster Session Abstracts May 23 - 24, 2016 Omni Richmond Hotel Richmond, Virginia Author Poster Number Abeyawardhane Dinendra L. T24 Akbarali Hamid M9 Allen Irving C. T19 Alwassil Osama I. T13 Argade Malaika D. T13 Asmar Anthony T27 Audette Michel T3 Aylor Kevin W. M2 Bagdas Deniz T15, T18 Balakathiresan Nagaraja T6 Banks Matthew L. M16, M19, M20, M21 Barrett Eugene J. M2 Bartsch Victoria T8 Bassaganya-Riera Josep T17 Baumann M. H. T2 Betz Heinrich M27 Bevan David M15, T5, T20 Bhomia Manish T6 Bickston Stephen T17 Blatt Jason E. T3 Bledsoe Douglas M27 Blough Bruce E. M20 Boroda Salome M25 Boulton Adam T10 Bowers Devin M28 Brown Anne M15, T20 Bruno Robert D. T26 Bullock Timothy T1 Burk Joshua T4 Bushweller John H. T10 Butman John T3 Cao Shugeng M14 Carbo Adria T17 Carlier Paul M22 Cetas Justin T3 Chen Keqiang M6 Cheng Kejun M21 Chojnacki Jeremy E. M17 Christian Phil M7 Coogle Constance M28 Cook James M16 Costa Blaise M27 Costa Anthony T3 Damaj Imad T15, T18 Daniel Dianne M5 Davalos Rafael T19 Davis Richey M24 De Felice L. J. T2 Dervisis Nikolaos T19 Dewey William M9, T7, T11, T12 Dukat Malgorzata T13 Ehrich Marion M18, T17 Electron Kebebew M14 Eltit J. M. T2 Ewend Matthew T3 Fadel Jim R. T4 Fauq Abdul M22 Fitzpatrick Mairen E. T6 Foster Johan M1 Franck Christopher T. T21 Fuss Babette M3 Gandour Richard T17 Gaskins Kelly M14 Gaultier Alban M10, T1 Gemta Leslie T1 Glennon R. A. T2 Godfrey Earl W. M5 Gonek Maciei T12 Gourdie Robert M1 Gray Sarah M2 Green Michael R. T22 Guan Ting T21 Guo Sujuan T22 Hallum Olga Y. T6 Hancock Sandy M18 Handing Kasia T10 Haq Rabia T3 Harris Robert M7 Harris Thurl E. M25 Heitger Denver R. M26 Heller Richard T27 Heller Loree T27 Helm Rich T5 Hontecillas Raquel T17 Hsu Ku-Lung T16 Hutsell Blake M21 Iyer Kavita T13 Jackson Asti T15, T18 Jacob Joanna T7 Jali Abdulmajeed T25 Jo Ami M24 Johnson Amy M20 Johnson Edward M. M5 Jurmain J.L. T14 Kayandan Sanem M24 Kelly Deborah F. T21 Kingston David M11, M14 Knudsen Giselle M13 Lamouille Samy M1 Laube Bodo M27 Lazo John S. T10 Lee Yueh T3 Li Liwu M6 Li Dai J. M7 Li Guanguan M16 Liang Yanping T21 Libutti Steven K. M14 Lile Joshua A. M20 Lippold Kumiko T11 Lister James A. M3 Liu Kai M17 Lucas Heather M26 Lucas Heather R. T24 Machida Mayumi T6 Mackey Zachary M13 Madry Christian M27 Maheshwari Radha K. T6 Malone Robert T9 Malone Jill Glasspool T9 Martin del Campo J. S. M11 McDevitt Jason M23, T23 McQueeny Kelley T10 Mesic Ivana M27 Meyers Gregory A. M7 Miles M. F. T14 Minor Wladek T10 Mollica Peter A. T26 Monceaux Christopher M22 Murphy Susan T22 Negus S. Stevens M16, M19, M20, M21, T2 Niccum Maria M25 Nicholson Katherine L. M20 Nilubol Naris M14 O’Hanlon Katherine A. M7 Obeng Samuel M12, T25 Ogle Roy C. T26 Paciotti Guilio F. M14 Pakhomov Andrei M4 Pan Xiaolei T13 Pang Priscilla T3 Partilla J. S. T2 Petrella Ross M4 Philipson Casandra T17 Philipson Noah T17 Pilitsis Julie T3 Poe Michael M. M16 Pridham Kevin T22 Purow Benjamin W. M1 Purow Benjamin W. M25 Qin Qizhi T19 Raje Vidisha M25 Rashid Tanweer T3 Ray Keith T5 Reid John A. T26 Reynolds Thomas M7 Rice Kenner C. M21 Richelson Elliott M22 Riffle Judy M24 Roberts Rose M1 Rosen Abagail M10, T1 Rossmeisl John M1 Ruchala I. T2 Russell Melissa M7 Saathoff John M17 Sachs Patrick T26 Sakloth F. T2 Salamoun Joseph M. T10 Sanford Larry D. T6 Schoenbach Karl H. M4 Schwienteck Kathryn M16, T2 Seki Scott M10, T1 Selley Dana M9 Selley Dana E. T25 Sharlow Elizabeth T10 Sheng Zhi M1, T21, T22 Slattum Patricia M28 Sobrado Pablo M11 Solis Jr. E. T2 Stacey Michael T27 Stevenson Max T1 Sultana Sharmin T3 Sutton Amy M. T6 Sweet Douglas T13 Tamarkin Lawrence M14 Tamer Ceyhun M27 Valenciano Ana Lisa M13 Varghese Robin T21 Velander Paul T5 Virbasius Ching-Man T22 Vogelaar N. M11 Wellman Laurie L. T6 Wheeler Natalie M3 Williams Brook T6 Williams Dwight M9 Wipf Peter T10 Wolz Gabriella M7 Wu Ling T5 Xiao Shu M4 Xu Guoyan M9 Xu Bin T5 Yang Hu M9 Young Richard M8 Yuan Ruoxi M6 Yuan Yunyun M9 Yuan ZiQiang M14 Zhai Min T6 Zhang Yan M9, M12, T25 Zhang Shijun M17, T5 Zhao Jielu M14 Zolotarskaya Olga M9 Zylka Mark J. T8 VirginiaBrainRx Poster Session M 1 TRANSLATION OF A NOVEL GLIOBLASTOMA DRUG TO CLINICAL TRIALS Robert G. Gourdie1,2,3, Johan Foster4, Rose Roberts4, Benjamin W. Purow5, John Rossmeisl6, Samy Lamouille1,7 and Zhi Sheng1,3 1Virginia Tech Carilion Research Institute, Roanoke, VA, 24016; 2Department of Biomedical Engineering and Mechanics, 3Virginia Tech Center for Drug Discovery; and 4Macromolecules Innovation Institute, Department of Materials Science and Engineering, Virginia Tech, Blacksburg, VA, 24061, 5Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, 22908, 6Department of Small Animal Clinical Sciences, VA-MD College of Veterinary Medicine and Hospital, Blacksburg, VA, 24061,7FirstString Research Inc., 300 W Coleman Blvd # 203, Mt Pleasant, SC 29464 [email protected] Glioblastoma (GBM) is the most common and deadly malignant brain tumor in adults. The standard-of- care treatment for GBM usually involves surgery to remove the tumor, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, this treatment is largely ineffective as tumors recur, with patients surviving an average of around a year. One of the main reasons for this failure is that patients develop resistance to TMZ chemotherapy. Our Virginia Tech team recently reported that the channel protein connexin43 (Cx43) is a key determinant of TMZ chemotherapy resistance in patients (Cancer Research, 76:139, 2016). Moreover, we showed that treatment with the Cx43 inhibitory peptide αCT1 recovered sensitivity of human GBM cells and glioma stem cells to TMZ in vitro and in GBM animal models. To advance αCT1 to human clinical testing for GBM we are pursuing two inter-related goals: Goal 1) Formulation of a controlled-release CT1: FirstString Research is presently testing αCT1 in Phase III clinical trials for chronic skin wounds (J Inv Dermatology (Nature), 135:289-98, 2015), where it is being applied in a topical gel formulation. A different strategy is required in dog and human clinical trials, wherein αCT1 will be delivered directly into tumors by convection-enhanced-delivery (CED). To achieve this, we have encapsulated αCT1 in poly(lactic-co-glycolic acid) nanoparticles (an FDA-approved vehicle), which provide for its controlled-release following CED injection. We have optimized nanoparticle size to <200 nm and have characterized release kinetics over 3 weeks at 37 °C and nanoparticle uptake and dissolution in cultured cells over similar time courses. Goal 2) To do a clinical trial in dogs with GBM tumors: Veterinary clinical tests are an invaluable tool in the study of human disease and its treatment. High-grade glioma/GBM occurs naturally at a similar frequency in dogs as it does in humans. Around 30 dogs are diagnosed with glioma each year in the Neurosurgery clinic at the Virginia Maryland School of Veterinary Medicine and Hospital. In collaboration with FirstString Research, our Virginia Tech team has obtained regulatory approval for clinical testing of oral TMZ in combination with CED of αCT1 into dog brain tumors - the FACT-CG clinical trial. The first of the canine patients entered the protocol in April 2016 and it is expected that 6 to 8 dogs will have received the combined treatment by Q4 2016. If safety outcomes from FACT-CG are favorable, we anticipate seeking regulatory approval from the FDA to advance to clinical trials in humans with GBM in Q1 2017. Acknowledgement: This research is supported by the Virginia Biosciences Health Research Corporation (VBHRC- the Catalyst), FirstString Research Inc, the Virginia Center for Innovative Technology (CIT) and Virginia Tech VirginiaBrainRx Poster Session M 2 INSULIN UPTAKE BY THE BRAIN ENDOTHELIAL CELL IS RECEPTOR-DEPENDENT AND BLUNTED BY HIGH-FAT DIET FEEDING Sarah M. Gray1, Kevin W. Aylor2, and Eugene J. Barrett1,2* 1Department of Pharmacology, University of Virginia, Charlottesville, VA 22908 2Division of Endocrinology & Metabolism, University of Virginia, Charlottesville, VA 22908 [email protected] Insulin access to the brain may be critical for appetite regulation, metabolism, and cognition1-4. Despite its importance, little is known of how insulin crosses the blood-brain barrier (BBB) to reach brain interstitial fluid and act on target neurons. We hypothesized that the BBB endothelial cell (BEC) has an insulin receptor-mediated vesicular transport system and that high fat diet (HFD)-induced insulin resistance could interfere with this process. To test whether insulin reaches brain tissue in vivo via the CSF circulation or by crossing the BBB, rats received 0.7 pmol 125I-insulin (125I-ins). Afterward, the vasculature was flushed for 5 min and brain tissue collected. 125I-ins appeared in cerebellum, cortex, and basal nuclei before reaching CSF. An insulin receptor selective antagonist (S-961) blocked brain 125I-ins clearance (p<0.01) as did 4 weeks of HFD (p<0.05, vs chow fed rats). We also isolated brain ECs from HFD and chow fed (ND) rats and measured 125I-ins uptake (200 pM). Again, HFD decreased EC 125I-ins uptake (p<0.01). A comparison of insulin receptor mRNA and protein expression showed no difference between ND and HFD BECs. To test whether canonical insulin signaling pathways were blunted in HFD rats, we stimulated isolated BECs with 10 nM insulin or vehicle control and western blotted for phosphorylated and total proteins.
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