EMBR-01_Gintvile Valinciute


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Gintvile Valinciute1,2, Jonas Ecker1,2, Florian Selt1,2, Thomas Hielscher3, Christin Schmidt4, Romain Sigaud1,2, Johannes Ridinger1,2, Charlotte Gatzweiler1,2, Daniel Picard5,6, Sina Oppermann1,2, Mirjam Blattner-Johnson1,7, David T. W. Jones1,7, Ina Oehme1,2, Marcel Kool1,8, Marc Remke5,6, Stefan M. Pfister1,4, Olaf Witt1,2, Till Milde1,2;

1Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. 2Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 3Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 5Department of Pediatric Oncology, Hematology and Clinical Immunology, Duesseldorf University Hospital, Duesseldorf, Germany. 6German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 7Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 8Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

BACKGROUND: Medulloblastoma (MB) is one of the most common malignant pediatric CNS tumors. Patients with Group 3 MBs harboring MYC amplification exhibit low survival rates. Surviving patients suffer from therapy-induced sequelae, which calls for new targeted therapy strategies. We and others have previously shown the sensitivity of MYC-amplified MB to class I histone deacetylase (HDAC) inhibition. After demonstrating that the MYC target gene PLK1 is significantly downregulated upon class I HDACi treatment, we hypothesized that inhibition of both HDACs and PLK1 could have synergistic effects. METHODS: Cell metabolic activity changes upon HDAC and PLK1 inhibitor treatment were measured in MYC-amplified and non-amplified MB cell lines, as well as in an additional MYC-inducible cell line. The interaction effect of both inhibitors was determined by computation of the combination index (CI) using the Chou-Talalay method. Results were validated assessing cell viability, cell cycle, and apoptosis induction. Transcription profile changes after combination treatment were evaluated. RESULTS: MYC-amplified MB cell lines were more sensitive than non-amplified cell lines to PLK1i treatment, showing IC50 in clinically achievable concentration ranges. Inhibition of class I HDACs and PLK1 synergistically reduced cell metabolic activity in lower concentrations in MYC-amplified compared to non-amplified MB cell lines. We also observed a significant loss of viability and cells in G1 phase, as well as induction of apoptosis after combination treatment in MYC-amplified cells. MYC target gene sets were significantly downregulated in the MYC-amplified cell line HD-MB03 after treatment with combination. We demonstrated reduction of MYC protein levels upon PLK1i treatment. In vivo evaluation of combination treatment using orthotopic Group 3 MYC-amplified MB PDX models is ongoing. CONCLUSION: Our data suggest that MYC-amplification is a predictive marker for PLK1i treatment in MB. The combination of HDACi and PLKi could be a candidate therapy for future clinical trials for MYC-amplified group 3 MB.

Duration: 04:48

Posted: Sunday, June 6, 2021

Video tags: 2021 SNO Pediatric Meeting