MODL-35. A NOVEL PATIENT-DERIVED TUMOR ORGANOID MODEL IDENTIFIES HDACI PANOBINOSTAT AS HIGHLY EFFECTIVE DRUG IN MENINGIOMAS

Tumor-organoids (TOs) are novel, complex three-dimensional ex vivo tissue cultures that under optimal conditions accurately reflect the genotype and phenotype of the original tissue with preserved cellular heterogeneity and morphology. They offer a new and exciting platform for studying cancer biology and directing personalized therapies. Our study aimed to establish TOs from meningioma (MGM) and explore drug responses of selected drugs.TOs were established by controlled reaggregation of freshly prepared single-cell suspension of MGM tissue samples in 384-well plates. We were capable of forming several hundred TO equal in size with a success rate of 98%. TOs consisted of largely viable cells, whereas dead cells were predominantly found outside of the organoid. H&E and IF stainings confirmed the successful establishment of dense tissue-like structures. On the molecular level, transcriptional and mutational profiles were conserved in TOs. To query the suitability and reliability of TOs for robust large-scale drug testing by employing nine highly potent compounds, derived from a drug screening performed on MGM cell lines. In total, standardized TOs from 60 patients were formed, including eight grade II and three grade III MGMs. The FDA-approved epigenetic drug panobinostat demonstrated high anti-meningioma effects in the majority of patients. The efficacy was mediated through inhibition of HDAC1/2 validated by siRNA-mediated knockdown experiments. In an orthotopic in vivo model, treatment with panobinostat extended the median survival of mice, however, the therapy was not curative. To further investigate HDACi resistance, transcriptomes of sensitive and resistant TOs were compared. In resistant tumors, a significant induction of the TGFβ pathway was observed.Taken together, we developed a protocol to generate standardized TO from MGM and preserved histological and molecular features of parental tumor. Drug screening of selected drugs in TOs from 60 patients identified HDACi panobinostat as effective drug through inhibition of HDAC1/2.