Grant: Operating Grant

Most chemotherapeutic agents used to treat cancers target growing (dividing) cells. Unfortunately, when these agents are used they can affect normal dividing cells, which can have devastating short-term and long-term effects. In this proposal we will attempt to understand how a particular cellular pathway, called the insulin-like growth factor 1 receptor (IGF1R) axis, contributes to tumour formation. IGF1R is activated in virtually all childhood malignancies, as well as many adult cancers and IGF1R blocking antibodies have shown impressive anti-tumor activity in childhood sarcomas and breast cancers. However, it remains a puzzle as to how IGF1R actually contributes to malignancy, and the basis for sensitivity versus resistance in different patients is completely unknown. We hope to learn how this signaling axis may be uniquely activated in tumour cells and how it might be more efficiently targeted therapeutically. As a model system, we will study an oncogenic protein called ETV6-NTRK3, which we originally discovered in childhood sarcomas and a form of breast cancer. ETV6-NTRK3-driven cancer cells are dependent on the IGF1R axis for survival. In the previous grant cycle we unexpectedly found that IGF1R stabilizes the ETV6-NTRK3 oncoprotein, and that when IGF1R is chemically blocked the levels of ETV6-NTRK3 protein are rapidly reduced. Therefore an exciting possibility is that IGF1R stabilizes oncogenic proteins in tumour cells. In this proposal we will directly analyze how IGF1R contributes to ETV6-NTRK3 stability. Inhibiting the kinases that control fusion protein stability is a novel way of selectively targeting cancers driven by oncogenic fusion proteins. Since kinase inhibitors for IGF1R are currently in clinical trials, we believe that findings from this proposal may have far-reaching relevance for the many different types of cancers driven by IGF1R-dependent oncogenic fusion proteins.