ATRT-19. PRECLINICAL EFFICACY OF COMBINED INHIBITION OF MEK AND MELK IN ATYPICAL TERATOID/RHABDOID TUMORS

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2018-06, Vol.20 (suppl_2), p.i31-i31
• Main Authors: Meel, Michaël, Navarro, Miriam Guillén, de Gooijer, Mark, Waranecki, Piotr, Petersen, Naomi, van Vuurden, Dannis, Kaspers, Gertjan, Hulleman, Esther
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy059.017

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant tumors of the central nervous system occurring predominantly in young children. Currently, the only curative therapeutic option consists of surgery combined with intensive chemo- and radiotherapy, often leading to severe long-term sequelae. Therefore, novel therapeutic strategies that reduce these sequelae while maintaining curative potential are urgently needed. Genetically, AT/RT is characterized by a biallelic inactivation of SMARCB1 or SMARCA4, causing aberrant chromatin remodeling and thereby expression of a variety of oncogenes. Recently, the importance of the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of AT/RT has been demonstrated, with preclinical efficacy of MEK inhibition in AT/RT cells. By in silico analysis of publicly available datasets we identified a strong overexpression of the Maternal Embryonic Leucine zipper Kinase (MELK) in AT/RT samples compared to normal brain and cerebellar tissue. Inhibition of MELK by the small molecule OTSSP167 strongly reduced proliferation and survival of primary AT/RT neurospheres. Combined treatment of primary AT/RT cells with OTSSP167 and the MEK inhibitor Trametinib showed strongly synergistic cytotoxicity at low nanomolar concentrations. Treatment of mice carrying newly developed primary, patient-derived VUMC-AT/RT-01-Fluc xenografts with the combination of OTSSP167 and Trametinib prolonged their survival and confirmed the reported synergy in vivo, even though both agents supposedly do not cross the blood brain barrier (BBB). Thus, besides demonstrating a novel potential therapeutic combination for AT/RT, these results indicate an, at least partially, functionally defective BBB in AT/RT, thereby suggesting the possibility to incorporate non-BBB penetrable drugs into therapeutic regimens for these tumors.