# Novel Compounds Target Aberrant Calcium Signaling in the Treatment of Relapsed High-Risk Neuroblastoma

## TL;DR

This study identifies new compounds that target abnormal calcium signaling in relapsed high-risk neuroblastoma, potentially offering a new treatment approach.

## Contribution

The paper introduces novel compounds that disrupt calcium signaling pathways unique to relapsed high-risk neuroblastoma.

## Key findings

- Compounds 248 and 249 induce cell death in HRNB by disrupting SOCE, ER, and mitochondrial signaling.
- These compounds activate unique calcium signals that lead to mitochondrial calcium overload and cell death.
- The findings suggest a new calcium-mediated cell death pathway for treating refractory HRNB.

## Abstract

High-risk neuroblastoma (HRNB) is an extracranial solid pediatric cancer. Despite the plethora of treatments available for HRNB, up to 65% of patients are refractory or exhibit an initial response to treatment that transitions to therapy-resistant relapse, which is invariably fatal. A key feature that promotes HRNB progression is aberrant calcium (Ca2+) signaling. Ca2+ signaling is regulated by several druggable channel proteins, offering tremendous therapeutic potential. Unfortunately, many of the Ca2+ channels in HRNB also perform fundamental functions in normal healthy cells, hence targeting them increases the potential for adverse effects. To overcome this challenge, we sought to identify novel Ca2+ signaling pathways that are observed in HRNB but not normal non-cancerous cells with the hypothesis that these novel pathways may serve as potential therapeutic targets. One Ca2+ signaling pathway that is deregulated in HRNB is store-operated Ca2+ entry (SOCE). SOCE relays the release of Ca2+ from the endoplasmic reticulum (ER) and Ca2+ influx via the plasma membrane and promotes cancer drug resistance by regulating transcriptional programming and the induction of mitochondrial Ca2+ (mtCa2+)-dependent signaling. mtCa2+ signaling is critical for cellular metabolism, reactive oxygen production, cell cycle, and proliferation and has a key role in the regulation of cell death. Therefore, a dynamic interplay between ER, SOCE, and mitochondria tightly regulates cell survival and apoptosis. From a library of synthesized novel molecules, we identified two structurally related compounds that uniquely disrupt the dynamic interplay between SOCE, ER, and mitochondrial signaling pathways and induce cell death in HRNB. Our results revealed that compounds 248 and 249 activate distinct aberrant Ca2+ signals that are unique to relapsed HRNB and could be exploited to induce mtCa+ overload, a novel calcium influx current, and subsequent cell death. These findings establish a potential new pathway of calcium-mediated cell death; targeting this pathway could be critical for the treatment of refractory and relapsed HRNB.