Abstract
Neuroblastoma is a rare disease. Rare are also the possibilities to test new therapeutic options for neuroblastoma in clinical trials. Despite the constant need to improve therapy and outcomes for patients with advanced neuroblastoma, clinical trials currently only allow for testing few substances in even fewer patients. This increases the need to improve and advance preclinical models for neuroblastoma to preselect favorable candidates for novel therapeutics. Here we propose the use of a new patient-derived 3D slice-culture perfusion-based 3D model in combination with rapid treatment evaluation using isothermal microcalorimetry exemplified with treatment with the novel carbonic anhydrase IX and XII (CAIX/CAXII) inhibitor SLC-0111. Patient samples showed a CAIX expression of 18% and a CAXII expression of 30%. Corresponding with their respective CAIX expression patterns, the viability of SH-EP cells was significantly reduced upon treatment with SLC-0111, while LAN1 cells were not affected. The inhibitory effect on SH-SY5Y cells was dependent on the induction of CAIX expression under hypoxia. These findings corresponded to thermogenesis of the cells. Patient-derived organotypic slice cultures were treated with SLC-0111, which was highly effective despite heterogeneity of CAIX/CAXII expression. Thermogenesis, in congruence with the findings of the histological observations, was significantly reduced in SLC-0111-treated samples. In order to extend the evaluation time, we established a perfusion-based approach for neuroblastoma tissue in a 3D perfusion-based bioreactor system. Using this system, excellent tissue quality with intact tumor cells and stromal structure in neuroblastoma tumors can be maintained for 7 days. The system was successfully used for consecutive drug response monitoring with isothermal microcalorimetry. The described approach for drug testing, relying on an advanced 3D culture system combined with a rapid and highly sensitive metabolic assessment, can facilitate development of personalized treatment strategies for neuroblastoma.
Highlights
Neuroblastoma arises from the sympathetic nervous system and is the most common solid tumor diagnosed in the first year of life [1]
carbonic anhydrase XII (CAXII) was positive in 30% of neuroblastoma samples on the Tissue Microarray (TMA) (n = 9/30)
We investigated if the inhibitory effect of SLC-0111 can be measured by using isothermal microcalorimetry to make possible rapid treatment evaluation
Summary
Neuroblastoma arises from the sympathetic nervous system and is the most common solid tumor diagnosed in the first year of life [1]. With an incidence of 1:7000 to 1:8000, neuroblastoma is the most common extracranial solid malignancy in children [2,3]. Neuroblastoma is a heterogenous malignancy with a wide spectrum of cellular subtypes ranging from epithelial-like tissues to neuronal tissues with a wide variety of clinical manifestations. Modern treatment strategies have led to increased survival rates, neuroblastoma still contributes to 15% of child deaths from cancer, and high-risk patients still face poor outcomes [2,3]. The reasons why tumors spontaneously regress or progress to multi-organ manifestation and chemoresistance is largely undetermined [4–6]. Despite recent advances through clinical studies, almost 80% of patients with advanced disease do not show sufficient response to treatment [7,8]
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