Tumor Angiogenesis in Different Organ Environments: Implications for Anti-VEGF Therapy for Soft Tissue Sarcomas

Anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) and other angiogenic pathways are a major focus of clinical drug development for cancers including soft tissue sarcomas (STS). An underlying premise of these trials is that VEGF inhibition will have equal efficacy in all sites of tumor growth and against all types of endothelial cells. This proposal seeks to develop an angiogenic profile of STS growing in different organs and tissues and to determine if inhibition of VEGF signaling will have varying effects on tumor angiogenesis in differen

Functional Genomic Characterization of a Conditional Mouse Model of Alveolar Rhabdomyosarcoma: Comparison to Human Tumors

Rhabdomyosarcomas are the most common childhood soft tissue sarcoma. We have developed a conditional mouse model of alveolar rhabdomyosarcomas by expressing the Pax3:Fkhr oncogene in skeletal muscle of juvenile mice. We propose to test that our mouse model mimics the secondary genomic and gene expression changes seen in human alveolar rhabdomyosarcomas. We will (1) compare chromosomal segment gains and losses in 8 mouse and 8 human alveolar rhabdomyosarcomas, and (2) correlate genomic imbalances of mouse and human tumors to gene expression changes of those same tumors. Understanding molecular events underlying tumor invasiveness and metastasis, we simultaneously identify potential therapeutic targets.

Immunologic Monitoring of Patients with Alveolar Soft Part Sarcoma Receiving a Long Translocation-Specific Peptide Vaccine with GM-CSF Adjuvant

We are developing a long amino acid peptide vaccine to be used with GM-CSF adjuvant to target the ASPL/TFE3 breakpoint translocation of alveolar soft part sarcoma (ASPS). We will address two specific aims: 1) Can CD8+ and CD4+ T-cell responses be generated to this vaccine by ASPS patients of different HLA haplotypes? 2) Can these general immune responses help determine HLA-specific immunogenic peptides for use in future trials? By using a long peptide sequence we can target patients of different HLA types as well as measure class I and class II responses to optimize future vaccines capable of destroying ASPS.

Development of a Mouse Model of Synovial Sarcoma

Synovial sarcoma is marked by a unique and specific translocation between the SYT and SSX genes resulting into the expression of the chimeric ‘SYT-SSX’ fusion protein. We are developing a mouse model of Synovial Sarcoma by conditional expression of the human SYT-SSX protein in mouse using the technique of gene targeting. Conditional expression will be achieved by utilizing the Cre-loxP system. This strategy will enable us to investigate into: a) origin of this disease. b) the role of SYT-SSX fusion protein in tumor induction/progression and c) downstream events during tumorigenesis. This model will also enable development/evaluation of novel therapeutic strategies.