Christine Pratilas, MD

Despite effective treatment options for many children with cancers, there is an unmet need for novel therapies to address some high-risk cancers that spread or grow despite our best available therapies. A major feature in cancer development is the accumulation of mutations, or changes, in the cellular DNA, which disrupt the normal function of cells and allow uncontrolled growth. In rhabdomyosarcoma (RMS), a common type of muscle cancer that affects children, mutations often occur in one of three RAS genes, HRAS, NRAS, or KRAS, and these result in signals that support tumor growth. We are researching ways to inhibit RAS in RMS tumors using targeted therapies, drugs that specifically act on mutant proteins but leave healthy cells intact. SHP2 is a protein in the cell that works with RAS to promote growth signals, and novel drugs targeting SHP2 have recently been developed and are being tested in adults with advanced cancer. We are therefore testing the ability of inhibitors of SHP2 to treat laboratory models of RMS, in both cell models (that also allow us to study molecular effects) and in mouse models (to test how the drug, given orally, can prevent tumors from growing in the mice). A lot of experience in using these types of drugs has taught us that often, the drugs can shrink the tumors, but the effects are short-lived and sometimes the tumors grow back. In order to deepen the responses that are seen, we will also test the combinations of the SHP2 inhibitor with three other types of drugs (FGFR inhibitor, PI3K inhibitor, and CDK4/6 inhibitor) to see if these drugs given together are better at preventing tumor growth. We hope our research will lead to the development of new clinical trials of targeted therapies to treat children with RAS-mutant RMS.