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The impact of the tissue context on tumor growth and drug response in medulloblastoma (MB) is poorly understood. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed the assessment of tumor cell behavior in the tissue context. To identify druggable kinase pathways involved in invasion, we screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB. Importantly, AURKBi are tumor suppressive in the tissue context, also in MB tumor cells that are in vitro resistant to the same treatment. We confirmed the requirement of AURKB for tumor growth and expansion in the tissue context through genetic suppression of AURKB by siRNA. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells. We demonstrate that tumor growth in the tissue context is suppressed by pharmacological inhibition of AURKB, comparable to the growth reduction observed after X-ray irradiation, which was used as the positive control. Finally, we show that exposure to µM concentrations of Barasertib does not cause developmental toxicity in fish larvae. In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.