Grant: Project Grant

Ewing sarcoma (EwS), the 2nd most common childhood bone sarcoma, is an aggressive tumour that primarily affects children, adolescents, and young adults. When EwS tumor cells spread to other parts of the body, known as metastasis, survival is drastically diminished to only 15-20%, which has not changed for decades. Immunotherapy (IT) empowers a patient's own immune system to attack cancer, which has tremendous promise as an alternative to chemotherapies that are often toxic, especially to a growing child. However, surface markers suitable for IT are very limited in EwS. It was first recognized nearly 100 years ago that cancer cells exploit distinct pathways to enhance their metabolism (i.e. use of nutrients to make energy and building blocks for cell growth) to support their cancerous features, such as unlimited growth capacity and the ability to spread and damage other organs. Proteins on the cell surface that help cancer cells maintain these unique metabolic features likely represent an "Achilles heel" for these tumours, which can potentially be exploited as IT targets using antibodies and cutting-edge cell-based therapies (dubbed a "living drug"). In a recent study, we searched for surface proteins that fit the criteria for promising IT targets in EwS. We identified the IL1RAP surface protein as being crucial for helping EwS cells maintain sufficient levels of cysteine, an amino acid metabolite that is critical for EwS cell survival and metastasis. Notably, only minimal IL1RAP is found in normal tissues except placenta, nominating IL1RAP as an ideal IT target with little chance of inducing toxicities in children with EwS. In this grant we will seek to develop and test a unique suite of cutting-edge IT reagents to target IL1RAP in EwS. With this approach, we will not only develop reagents to target a key EwS metabolic regulator for IT, we will also optimize strategies to reduce or reverse local immunosuppression that otherwise is known to hinder IT efficacy in EwS.