1.O.08 CURRENT CONCEPTS ON THE MOLECULAR BIOLOGY OF OSTEOSARCOMA

Abstract

Osteosarcoma despite considerable biological and molecular heterogeneity, being defined by a phenotypic program resulting in the production of osteoid, is a relatively consistent clinical entity. Over the past 20 years a large catalogue of genetic alterations present in osteosarcoma has been compiled, but unfortunately this information has yielded little biological understanding or widely accepted prognostic factor. In an analogous manner nearly two decades of clinical trials, most incorporating new agents or intensifying therapy have not further improved the prognosis of patients with osteosarcoma. This would lead to considerable pessimism if it were not for the dramatic expansion in availability of osteosarcoma models, tissues resources as well as new agents, particularly antibodies targeted to various cell surface receptor proteins. Selecting and applying these agents will require an understanding of osteosarcoma’s unique dependencies and may also have the potential to yield biological insights. Defining these dependencies has been complicated by osteosarcoma’s genetic complexity as well as redundant expression of cell surface receptors, but efficacy of antibody-based targeted therapies may assist in defining the relative importance of receptors as well as their downstream signal transduction pathways. The availability of these new tissue resources and murine models may assist in understanding osteosarcoma’s complex biology, aid identification of biological features that can serve as prognostic factors as well as assist in the selection of new agents for clinical trials. These new resources may permit one to define the feasibility of performing a biologically based treatment selection and may have implications for cooperative group interaction. During this presentation the molecular biology of osteosarcoma will be reviewed, the available tissue resources and models will be outlined, some of the preliminary data available thus far will be presented, and this will be placed in the context of ongoing as well as planned phase 1 and phase 2 osteosarcoma clinical trials.