Molecular Targeted Agents and Signal Transduction Inhibitors
Sarcomas are a microcosm of solid tumor oncology: different sarcomas are increasingly being defined by molecular signatures and biological characteristics rather than by simple histopathology. Our group is translating this research on the basic biology of sarcomas into new therapeutics directed at novel targets. The foremost example of our team's work has been the development of tyrosine kinase inhibitors as effective therapies for patients with gastrointestinal stromal tumor (GIST). By targeting the specific molecular signals of GIST, we have validated the concept that a human solid tumor can be treated by signal transduction inhibitors. This work led to the development and FDA approval of imatinib mesylate (Gleevec) as an effective therapy for patients with metastatic or unresectable GIST, and underlies our ongoing research in other novel agents, such as the kinase inhibitor SU11248. Another example of molecular targeting of sarcomas in drug development is our pioneering interest in differentiation therapy for patients with liposarcomas. This research targets a nuclear receptor known as PPAR-gamma, which plays a role in the normal development of fat cells, and induces differentiation in liposarcomas to decrease proliferation. Larger studies based on our pilot data are now being designed to test the clinical value of this treatment, which we are refining with newer agents and methods.Our group also is developing other agents against sarcomas, such as the natural product known as ET-743, derived from a marine organism. This drug, which binds to the DNA minor groove, has shown important clinical activity against several subtypes of sarcomas both in the laboratory and in extensive clinical trials. We are optimizing the dosage for this agent and moving forward in collaboration with other cancer centers to test the worth of this new drug.Our multidisciplinary research team, including dedicated representatives from surgical oncology, radiation oncology, pathology, and other clinical arenas, works closely with laboratory investigators so that we can offer promising treatments of scientific merit to patients with sarcomas of soft tissue and bone.