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"Cage fighting" with Neuroblastoma: Engineering a protein nanocage for targeted ionophoric-copper therapy

Project Member(s): Care, A.

Funding or Partner Organisation: Cancer Australia (Priority-driven Collaborative Cancer Research Scheme)
Cancer Australia (Priority-driven Collaborative Cancer Research Scheme)

Start year: 2020

Summary: Neuroblastoma is the most common extracranial solid tumour in early childhood, and originates in the tissues that form the sympathetic nervous system. Despite aggressive treatments, neuroblastomas account for ~15% of paediatric cancer deaths. Thus, more effective treatments for this condition are critical. One therapeutic target for the treatment of neuroblastoma is copper. Evidence shows that elevated levels of copper drive tumour progression and metastasis in various cancers. Moreover, neuroblastoma cells exhibit higher levels of intracellular copper than non-malignant cells, making neuroblastoma susceptible to copper-based treatments. Ionophoric-copper therapy utilises ionophores that bind copper and deliver it into tumour cells, where it induces oxidative stress that causes cell death. Despite promising pre-clinical studies suggesting efficacy, safety and anticancer activity, no copper-ionophores have been approved to treat cancer. This is due to high toxicity, poor biostability and low bioavailability, and/or the off-target accumulation of copper in healthy tissues. Copper toxicity impairs musculoskeletal and brain development, which is of particular relevance for paediatric neuroblastoma patients, who are in a vulnerable period of their development. Therefore, although therapies directed at elevated levels of intracellular copper may be effective, better strategies must be developed to target the delivery of copper to tumour cells exclusively, enhancing therapeutic efficacy and reducing side-effects. To address this issue, we aim to take encapsulin protein nanocages from nature and re-engineer them into biologically-derived copper-ionophores, that selectively target the delivery of copper to neuroblastomas. By targeting tumour cells and eliminating adverse side-effects, this project will provide a disruptive technology that will advance the clinical use of copper-ionophoric therapy to treat neuroblastoma and other copper-rich cancers.

FOR Codes: Treatment of human diseases and conditions, Nanomedicine, Cancer therapy (excl. chemotherapy and radiation therapy), Synthetic biology