Precision Lethality to overcome clonal heterogeneity in high-risk neuroblastoma

ongoing

Tumors are heterogeneous in nature due to genetic instabilitTumors are heterogeneous in nature due to genetic instability, ongoing selection, and variable microenvironments with local adaptation. Many tumors thus necessitate combinatorial drug treatments to reach all cells. This is true also for neuroblastoma, the most common extracranial solid pediatric tumor. Despite the well-known importance of clonal heterogeneity, most in vitro drug combination strategies, including commonly used synergistic interaction, do not quantify subclonal drug response. Here recently developed cell barcoding strategies will be used to monitor survival of thousands of individual subclones in neuroblastoma organoids, under different drug perturbations. This lineage tracing strategy allows identification of cell populations that survive a specific drug, and to find other drugs that specifically target those cell populations. I call this strategy “Precision Lethality”. In this research program two different precision lethality methodologies will be developed, one where cell barcoding is used to identify drug combinations with low cross-resistance, and one that uses the possibility to express the barcode so it can be captured by single cell RNA sequencing. This allows assessing the transcriptional state before drug perturbation of cells that are known to be either drug resistant or drug sensitive. Combined with publicly available drug sensitivity data repositories, this will be used to construct a deep learning model to predict drug sensitivities of individual cells. Successful completion of this multi-disciplinary research program will identify and verify new drugs to complement standard of care consolidation therapy for neuroblastoma. I also envision that these studies will showcase to the broader cancer research community how cell barcoding can be used as a drug combination strategy to overcome clonal heterogeneity, which would increase the chances of finding curative cancer treatments.