Although both craniofacial and appendicular osteosarcomas are diagnosed under the rubric of osteosarcoma, their clinical phenotypes are actually distinct. Comparison of patterns of LOH have shown that primary craniofacial osteosarcoma is a different disease from appendicular osteosarcoma. This is likely the result of the developmental pathways by which the bones of craniofacial and appendicular skeleton arise;the craniofacial bones arise from cranial neural crest cells while the appendicular skeleton arises from mesenchymal-derived cells. Chemotherapy treatment leads to vastly different morbidity outcomes - craniofacial patients have a40% survival rate compared to an 80% survival rate for appendicular osteosarcoma. Given the outcome with conventional agents for this disease, there is clearly a need to develop a more informative classification systems by employing comprehensive analytical techniques to identify new potential targets for therapy. A molecular-based classification scheme identifying alterations in unique pathways in each tumor type identify such possible therapeutic targets. Differences between craniofacial and appendicular tumors should be detectable as quantitative and qualitative alterations in gene expression levels that together constitute definitive molecular signatures. The central hypothesis of this proposal is that these molecular signatures will correlate with clinical phenotype. A corollary hypothesis is that these molecular signatures will identify differentially regulated pathways in the tumors that may serve as targets for alternative therapies.
The specific aims for this proposal are: 1. Generate molecular signatures of primary appendicular and craniofacial osteosarcoma tumor samples by cDNA microarray analysis. 2. Correlate the molecular signatures with alterations in pathways. The ability to distinguish craniofacial osteosarcomas from appendicular osteosarcomas should have a positive impact on understanding the molecular basis of the disease and accelerate development of new treatments. This work is therefore likely to have an impact on the clinical management of osteosarcoma patients. My career goal is to become an independent dental research scientist in the field of molecular genetics or cancer genetics. In these next five years, I hope to attain and develop the necessary skills to achieve my aspiration. This training experience will help strengthen both my laboratory bench technique and application of the scientific method. With a sound foundation, I may be able to have an impact on some of my other areas of scientific inquiry - squamous cell carcinoma and fibrous dysplasia. I enthusiastically strive to become a more effective scientist with the hopes of one day making a significant contribution to the field of craniofacial biology.
