A Novel Genetically Engineered Mouse Model for Angiosarcoma: Molecular Characterization and Comparison to Human Angiosarcoma to Develop Targeted Therapy

Lionel Mu-Lo Chow, MD, PhD,  Cincinnati Children’s Hospital Medical Center
Recipient of the: $50,000 Pittsburgh Cure Sarcoma Co-Founder Bill Suit Research Award

Angiosaroma is a rare and aggressive sarcoma of childhood and adults with a very poor overall survival of 25% at 5 years. No effective systemic therapy has been described for this disease. Little research has been done on this entity as very few preclinical models exist with which to study the disease. We have developed the first genetically engineered mouse model for angiosarcoma that incorporates some of the known driver mutations and pathways involved in tumorigenesis. The model is robust with complete penetrance and tumors arise predominantly in the skin, allowing for accurate temporal tracking of tumor progression. The model is therefore ideal for preclinical testing of novel therapeutic interventions. In fact, we have determined that combinations of targeted therapy directed against the mTor and Mek protein kinases can effectively and durably suppress tumor growth in our model. In order to translate our results to patients with angiosarcoma, we propose to conduct a comprehensive genomic, transcriptomic and immunohistochemical analysis of pediatric vascular tumors compared to our novel animal model. We hypothesize that interspecies comparison of mutations, gene expression patterns and pathway activation markers will identify a subset of patients with aggressive vascular tumors, such as angiosarcoma and lymphangiosarcoma, who will benefit the most from this combination of inhibitors. Our study will include whole-exome sequencing of a cohort of pediatric vascular tumors to look for driver mutations. This information will be compared to the limited published data from adult patients that suggest the involvement of PI3K and MAPK pathways in tumorigenesis. We will also generate gene expression profiles by RNASeq from pediatric and murine tumors. This data will be analyzed to determine how closely tumors arising in mice recapitulate the molecular phenotype of human tumors. We will also conduct pathway analysis of tumors by RNASeq as well as by immunostaining techniques (immunohistochemistry and western blotting) to determine the involvement of PI3K and MAPK pathways in the growth and survival of tumors. We anticipate that this study will lead to the development of a multi-institutional clinical trial for this population of patients for whom very few treatment options currently exist.