Abstract 3892: High-throughput combination screen for identifying novel therapies against high-risk neuroblastoma

Abstract

Abstract Neuroblastoma is a childhood solid tumor commonly located in the adrenal gland. High-risk neuroblastoma patients undergo multidrug and multi-interventional treatment but despite these efforts many patients develop resistance to chemotherapy and eventually relapse. Neuroblastoma patients face an urgent need of novel therapeutic strategies that could effectively combat the disease. In a recent study we identified kinesin spindle protein (KSP) as a highly effective target in high-risk neuroblastoma. Pharmacological inhibition of KSP resulted in complete regression of a subset of neuroblastoma subcutaneous PDX tumors and tumor growth delay in orthotopic PDXs (Hansson, Radke et al, Sci. Transl. Med 2020). The purpose of the present study is to identify novel synergistic drug combinations effective against neuroblastoma and investigate their translational potential. We designed, optimized, and performed a high-throughput combination screen using 3D tumor organoids that represent three MYCN-amplified neuroblastoma tumors. KSP inhibition was tested in combination with the FIMM drug set of 527 approved and investigational drugs. Screening was performed stepwise: • Step 1: High-throughput drug screening 527 drug combinations and machine learning prediction (DECREASE tool) of drug combination synergy based on minimal required input. • Step 2: Screening of 6x6 dose-response matrices of top 26 predicted hits in high-risk neuroblastoma models. • Step 3: Screening of 6x6 dose-response matrices of top 26 hits in CD34+ cord blood controls to identify compounds that have low toxicity towards proliferating fraction of hematopoietic cells. Overall, we identified seven drug candidates (P1-P7). They classify as: kinase inhibitors, differentiating modifiers, and one hormone therapy. Screened combinations were chosen based on selective efficacy (difference between anti-neuroblastoma efficacy and efficacy towards CD34+ cord blood controls). Identified drug combinations are common among three high-risk neuroblastoma models and have most synergistic area score (MSA) over five. We further plan to validate seven hits in neuroblastoma models in vitro, investigate MOA of the most promising combination and test it in PDX models in vivo. Citation Format: Katarzyna Radke, Karin Hansson, Jani Saarela, Aleksandr Ianevski, Philipp Ianevski, Aurélie Baudet, Mattias Magnusson, Daniel Bexell. High-throughput combination screen for identifying novel therapies against high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3892.