Preclinical Studies of Gli1 Inhibition in Ewing Family Tumors

Ewing’s Sarcoma Family Tumors (ESFT) are aggressive tumors of bone and soft tissue which are mostly confined to childhood and adolescence. Even with intensified chemotherapy, approximately 40% of those diagnosed with ESFT will die of the disease. Despite intensive study into the molecular-level mechanisms of these tumors, remarkably little of use to patients has resulted. My lab has just published findings that demonstrate that a mechanism common to many adult cancers, also plays an important role in ESFT. This mechanism is called the Hedgehog-Gli pathway. Because this mechanism is so widely important in many cancers, multiple therapies are in development to treat cancer by inibiting this pathway. Some of these may be of potential benefit in ESFT treatment. Their use in these patients depends on the foundation that will be laid by this proposal. To demonstrate the potential usefulness of drugs which inhibit Hedgehog-Gli, we will test the effect of specific Gli inhibition in established in vivo model systems of ESFT. These methods of inhibition have already been developed in my lab. To further explore the utility of Gli1 inhibition, we will assess its effects on the chemotherapy sensitivity in ESFT cell lines. These data will allow us to make appropriate use of our laboratory findings and offer a new direction in the therapy of this deadly tumor.