Identifying native and heteroclitic epitopes for T-cell immunity to PAX3-FKHR alveolar rhabdomyosarcoma

Identifying native and heteroclitic epitopes for T-cell immunity to PAX3-FKHR alveolar rhabdomyosarcoma

Advanced liposarcoma has low overall response rates to chemotherapy. There is a need for targeted therapy for liposarcoma. Utilizing microarray and RT-PCR data, we found ribonucleotide reductase M2 (RRM2) to be upregulated in our liposarcoma cell lines and tumor samples. Triapine, (3-Aminopyridine-2-carboxaldehyde-thiosemicarbazone) and hydroxyurea are ribonucleotide reductase inhibitors that exhibit anti-proliferative activity in epithelial and hematological malignancies. We have an attenuated herpes simplex virus that requires host cell ribonucleotide reductase to replicate. We hypothesize that RRM2 is a novel target for both chemotherapeutic agents and biological viral agents in the treatment of liposarcoma and plan to validate in the laboratory…  Read More »

Identifying native and heteroclitic epitopes for T-Cell immunity to PAX3-FKHR alveolar rhabdomyosarcoma

Aveolar rhabdomyosarcoma is an aggressive muscle tumor of childhood for which recurrent or metastatic disease carries a poor prognosis and novel therapies are needed.  It is characterized most commonly by the oncogenic fusion protein PAX3-FKHR which represents a novel antigen and, therefore a potential target for immunotherapy. This study will use in vitro priming assays on human cells to address two specific aims to: 1) Identify for given HLA haplotypes any PAX3-FKHR breakpoint-spanning peptide that can generate CD8+ or CD4+ response and 2) Test predicted heteroclitic epitopes for PAX3-FKHR for their ability to activate CD8+ or CD4+ T cells.

Ribonucleotide reductase as a novel target in liposarcoma

Advanced liposarcoma has low overall response rates to chemotherapy. There is a need for targeted therapy for liposarcoma. Utilizing microarray and RT-PCR data, we found ribonucleotide reductase M2 (RRM2) to be upregulated in our liposarcoma cell lines and tumor samples. Triapine, (3-Aminopyridine-2-carboxaldehyde-thiosemicarbazone) and hydroxyurea are ribonucleotide reductase inhibitors that exhibit anti-proliferative activity in epithelial and hematological malignancies. We have an attenuated herpes simplex virus that requires host cell ribonucleotide reductase to replicate. We hypothesize that RRM2 is a novel target for both chemotherapeutic agents and biological viral agents in the treatment of liposarcoma and plan to validate in the laboratory…  Read More »

Blocking SYT-SSX Activities Using an Inhibitory Peptide

The long-term goal of this research is to understand the role of syt-ssx gene product in synovial sarcoma pathogenesis, and to develop novel and effective treatment for the disease. The cause of synovial sarcoma is unknown. However, a characteristic fusion of two genes, syt and ssx, has been identified. We have recently discovered a peptide that blocks SYT function in vitro. Based on the finding, I propose to further determine if this peptide is able to target SYT-SSX and block its activities in vivo. This may eventually lead to the discovery of novel treatment for synovial sarcoma.

Cancer stem cells and sarcoma

In this proposal we will test the hypothesis that the physiologic progenitor cell of mesodermal derivatives, the mesenchymal stem cell (MSC), is the cell of origin for a diverse population of sarcomas. We will isolate MSC based upon their functional activation of a marker gene (GFP) through Wnt/beta-catenin signal transduction. We will test a highly enriched MSC population for clonal self-renewal in vitro, and for tumor initiating capacity in vivo. The objective of this proposal is to create a xenogenic model of human sarcoma in the immune deficient Rag2 mouse for studies on the initiation/promotion of sarcoma.

Early identification of chemoresistant patients for improved risk-based therapy in pediatric osteosarcoma

Osteosarcoma is the most common malignant bone tumor in children. The survival rate for patients with resistance to standard chemotherapy is about 40%. The poor prognosis of chemoresistant patients indicates that new paradigms are needed to identify those patients up front, so that new treatment options can be offered initially to improve their outcome. Using a proteomic approach, we have identified two circulating biomarkers that are significantly correlated with chemoresistance. In this proposal, we plan to validate these two chemoresistant biomarkers and construct a bioinformatic model to identify chemoresistant osteosarcoma patients at initial diagnosis using sera collected in a national…  Read More »

Discovery of small molecule inhibitors of the MDM2-ubcH5 interaction

We will discover small molecules that disrupt the interaction between the oncoprotein MDM2 and UbcH5, its partner E2 ubiquitin conjugating enzyme. Such compounds will disrupt the E3 ligase function of MDM2 and are likely to inhibit its oncogenic functions, both those that are p53-dependent and p53-independent. The aims are: (i) to perform an in silico screen for compounds that disrupt E3-E2 interactions, and (ii) to test predicted inhibitors in high-throughput in vitro and cellular ubiquitination assays using MDM2/UbcH5. Inhibitors of the MDM2-UbcH5 interaction could ultimately be developed into novel therapeutics for sarcomas, which frequently involve amplification of the MDM2 oncogene.