ET 34. TAE226, A NOVEL Minimal MOLECULAR Bodyweight INHIBITOR OF FOCAL ADHESION KINASE, INHIBITS GLIOMA Growth Qing Shi,1 Anita B. Hjelmeland,1 Stephen T. Keir,one Sarah K. Wickman,1 Guanghong Wu,one Dowdy Jackson,two Osamu Ohmori,2 Darell D. Bigner,one,3 Henry S. Friedman,one,3,four and Jeremy N. Rich1,5,6, Departments of 1Surgery, 3 Pathology, 4Pediatrics, 5Medicine, and 6Neurobiology, Duke University Health-related Center, Durham, NC, USA, 2Novartis Institutes for Biomedical Analysis, Cambridge, MA, USA, Novartis Pharmaceuticals Oncology, East Hanover, NJ, USA. Glioblastomas are tremendously lethal cancers that resist present therapies. Glioblastomas commonly overexpress the nonreceptor tyrosine kinase, focal adhesion kinase, which contributes to tumor malignancy by raising cellular migration, invasion, and proliferation. We evaluated the efficacy of the novel lower molecular weight inhibitor of FAK, TAE226, against human glioma cell lines and xenografts.
TAE226 inhibited the phosphorylation of FAK plus the downstream effectors AKT, extracellular signal connected kinase, and S6 ribosomal protein. TAE226 demon strated a concentration dependent lessen in cellular proliferation with an associated G2 cell cycle arrest in multiple glioma cell lines. TAE226 also induced apoptosis when reducing cellular adhesion, migration, selleck and invasion in vitro, demonstrating the possible advantage of TAE226 in glioma treatment. In vivo, orally administered TAE226 ABT751 induced a modest development delay of sub cutaneous human glioma xenografts grown in immunocompromised mice. TAE226 also enhanced the survival of immunocompromised mice bearing orthotopic intracranial human glioma xenografts until finally neurologic deficits occurred.
As glioma xenografts depend largely on proliferative growth in lieu of invasion for tumor growth and FAK plays a major function in tumor invasion, these success might underestimate the efficacy of TAE226 in humans. For that reason, more evaluation of TAE226 and related FAK inhibitors alone and in mixture with other established therapies

for the treatment of glioblastoma patients is warranted. This study was supported in part by funds from the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure, Childhood Brain Tumor Foundation, and Southeastern Brain Tumor Foundation. This work was also sup ported by National Institutes of Health grants NS047409, NS054276, and 1 P50 CA108786. A. B. H. is a Paul Brazen/American Brain Tumor Association Fellow. J. N. R. is a Damon Runyon Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Cancer Foundation Scholar. ET 35. EFFECT OF DOSE AND SCHEDULING OF EMD 121974 ON Development OF ORTHOTOPIC GLIOBLASTOMA IN NUDE MICE Atsushi Suzuki,1 Shinya Yamada,1 Vazgen Khankaldyyan,one Anat Erdreich Epstein,1 Fred Dorey,one Ignacio Gonzalez Gomez,one Simon L.