Abstract 2625: Patient derived organoids to guide personalized neuroblastoma treatment
Authors: Rosati Rachele , Swan Hallie A. , Scolaro Laura , Krytska Kateryna , Maris John M. , Schaub Franz X. , Grandori Carla 
Published: August 2018

Abstract
Goal: Neuroblastoma (NBL) is the second most frequent pediatric solid tumor. We have seen an increase in survival for children with NBL, however treatment still consists of many cycles of chemotherapy and radiation. We reasoned, that in vitro high throughput drug screening (HTDS) of patient derived organoids using a library of targeted therapies, would highlight novel targeted and personalized treatment options.
Methods: We optimized an in vitro 3D culture for high-risk NBL samples, initially established as patient derived xenografts (PDX) and screened a total of 10 patient samples with genomic information using two different drug libraries: Informer Set (320 drugs) compiled by the Cancer Target Discovery and Development network which is focused on cancer pathways and SEngine Library (123 drugs) focused on clinically relevant therapies. The screen was performed in a 384 well-format and cell viability was measured. Organoids were characterized by immunohistochemistry and genomic and pathway alterations were confirmed.
Results: Here we highlighted unique results from 4 cases. The first sample showed sensitivities to CDK inhibitors in concordance with amplification of CDK4. However, for this patient additional drug sensitivities were not directly linked to a genetic alteration, such as AZD7762 (CHK inhibitor) and MK-1775 (WEE1 inhibitor) indicating sensitivities in the cell-cycle checkpoints, and an exceptional response to Enzalutamide, an androgen receptor antagonist. The second case had unique sensitivities to IGF1R and Insulin Receptor inhibitors (Linsitinib and BMS-754807) indicating a specific addiction to this growth-factors/survival signal. The third sample had multiple sensitivities linked to genomic alterations, such as
Dabrafenib, concordant with the presence of a BRAF activating mutation. In addition, sensitivity to Alisertib was detected as previously reported for MYCN amplified NBL, but this was not true for other MYCN amplified cases. Interestingly, this third sample also showed profound sensitivities to PARP inhibitors, most likely related to a mutation in the BRP1 gene a BRCA1 interacting protein gene. The fourth case showed a strong sensitivity to nutlin-3 (MDM2 inhibitor) and Oxaliplatin.
Conclusion: A newly established NBL 3D patient organoid culture system coupled with personalized HTDS and genomic analysis offers an effective platform for the discovery of novel personalized therapies and drug combinations tailored to individual patients. In this NBL cohort, we discovered both drugs predicted by the patient-specific genomic alterations, as well as novel patient-specific drug sensitivities without a known genomic marker. More in depth genomic analysis is underway, but epigenetic alterations could explain these exceptional responses. In summary, this investigational study of 10 NBL highlights the need of personalization of targeted therapies in NBL.
Citation Format: Rachele Rosati, Hallie A. Swan, Laura Scolaro, Kateryna Krytska, John M. Maris, Franz X. Schaub, Carla Grandori. Patient derived organoids to guide personalized neuroblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2625.