Osteosarcoma (OS) is the most common primary bone neoplasm in people and up to 30% of those diagnosed will not survive 5 years with current, multimodal therapy. This high-grade tumor most frequently affects adolescents and young adults, often requiring surgery, chemotherapy and, in some cases, radiation therapy. With no improvements in survival times made over the past 30 years, novel forms of therapy are desperately needed to improve outcomes for these patients. Runt-related transcription factor 2 (RUNX2) and core binding factor beta (CBF?) are members of a heterodimeric transcription factor complex involved in organized skeletal development. Their normal activities are dysregulated in OS, as well as in other cancers, and they have both been implicated in development and progression of human cancers. This project aims to identify the importance of the interaction between these two proteins for the malignant phenotype of OS, and use this information to uncover novel therapeutic targets. This will be accomplished through the use of allosteric inhibitors of CBF? that prevent RUNX2 binding and disrupt the transcriptional complex.
The Specific Aims of this project will 1) Determine the importance of the CBF?-RUNX2 interaction for the malignant phenotype of osteosarcoma, and 2) Identify molecular mechanisms resulting from disruption of the CBF?-RUNX2 interaction that induce an anti-tumor effect. A combination of in vitro assays and incorporation of patient-derived xenograft murine models of OS will help to identify how CBF?-RUNX2 mediates OS cell survival and dissemination. Mechanistic studies will be used to identify the critical genes and pathways that are important in promoting the malignant phenotype and are mediated by CBF?-RUNX2interaction. Transcriptomics and proteomics will be performed following inhibitor treatment and these data sets will be integrated and analyzed to uncover novel therapeutic opportunities for further investigation. The use of a novel canine PDX model of OS in this proposal will help provide the validation needed to justify future investigations of these findings in a pre-clinical model of spontaneously occurring OS. These studies will guide the career development of Dr. Luke Wittenburg by providing expertise in advanced molecular techniques, bioinformatics and integration of ?omics? data sets, and advanced murine models of human cancer. This project will be performed within the collaborative, ?One Medicine? centered environment at the University of California, Davis under the mentorship of internationally renowned experts in their respective fields; Dr. Xinbin Chen, Dr. C. Titus Brown and Dr.
Aimi ng Yu. This will position Dr. Wittenburg to attain his career objective of becoming a successful independent researcher who is competitive for extramural funding and a cornerstone of a productive and impactful developmental cancer therapeutics research program.
Osteosarcoma is the most common primary bone cancer in humans and survival improvements have not been attained in three decades; the majority of patients still succumb to metastatic spread. Identification of novel targets in osteosarcoma will be required to advance treatment of this ultimately fatal disease. This project will define the role of protein interactions between members of a critical transcriptional complex, improving our understanding of the biology of osteosarcoma and providing an information base for identification of novel targets and treatment combinations.
