A one-two punch therapeutic strategy to overcome chemotherapy-induced cell plasticity in neuroblastoma
Project Member(s): Carter, D., Gallego Ortega, D., Beck, D.
Funding or Partner Organisation: National Health & Medical Research Council (NHMRC - Ideas Grants)
National Health & Medical Research Council (NHMRC - Ideas Grants)
Start year: 2024
Summary: Neuroblastoma is an aggressive solid cancer of early childhood accounting for 15% of child cancer lethality. Despite high-intensity combination chemotherapy, drug resistance in neuroblastoma arises when minor cancer-subclones evolve to withstand the cytotoxic action of anticancer drugs. We have used longitudinal single-cell RNA-sequencing (scRNA-seq) of patient tumours to show that neuroblastoma is characterised by multiple interconnected malignant cell types. Throughout treatment, cellular transcriptomes are plastic, and cells adapt according to tumour-specific drug evasion trajectories. This highlights the need for individualised treatment strategies that account for cell plasticity. In this project, we will use cutting edge single-cell technologies including longitudinal profiling and lineage tracing to describe cell plasticity and drug resistance in neuroblastoma. We will utilise these data for development of a novel one-two punch based targeted therapy testing against chemotherapy-adapted cells in patient-derived models of neuroblastoma. Our findings will allow for better patient risk prediction in the clinic and a new generation of individualised therapies for high-risk neuroblastoma. Hypothesis: In neuroblastoma, we can exploit cell plasticity mechanisms underlying chemotherapy escape for better selection of individualised targeted therapy Aim 1: Use CellTag lineage tracing to reveal drug resistance mechanisms of plastic cancer subclones Aim 2: Use patient-derived models to test targeted combination therapy against chemotherapy adapted tumour phenotypes Aim 3: Predict neuroblastoma patient risk during frontline therapy in the clinic using a scRNA-seq based classifier of tumour plasticity This project is an innovative approach to dissect complex mechanisms of cell plasticity and drug resistance, leading to novel therapeutic options for neuroblastoma and better prediction of at-risk patients in the clinic.
FOR Codes: Expanding knowledge in the biomedical and clinical sciences, Cancer cell biology, Genomics and transcriptomics, Cancer therapy (excl. chemotherapy and radiation therapy)
