Research Grants

2006 SFA Research Grant Recipients

Discovery of small molecule inhibitors of the MDM2-ubcH5 interaction

• Brent R. Stockwell, Ph.D. Columbia University
• Recipient of a $25,000 Bradley J. Breidinger Memorial Research Award
• Abstract: 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.
• Final Report: Click to view PDF

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

• Tsz-Kwong Man, Ph.D. Baylor College of Medicine
• Recipient of a $25,000 Shelby L. Richter Memorial Research Award
• Abstract: 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 collaborative study.
• Final Report: Click to view PDF

Cancer stem cells and sarcoma

Karl Sylvester, M.D. Stanford University
• Recipient of a $25,000 Seth A. Bailey Memorial Research Award
• Abstract: 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.
• Final Report: Click to view PDF

Blocking SYT-SSX activities using an inhibitory peptide

• Yuechueng Liu, Ph.D. University of Oklahoma Health Sciences Center
• Recipient of a $25,000 Paul M. Rumely Memorial Research Award
• Abstract: 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.
• Final Report: Click to view PDF

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

Stacie Goldberg, M.D. Memorial Sloan Kettering Cancer Center
• Recipient of a $25,000 Brian J. Monaghan Memorial Research Award
• Abstract: 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 RRM2 as a new target for the treatment of liposarcoma.
• Final Report: Click to view PDF

Ribonucleotide reductase as a novel target in liposarcoma

• Rula Geha, M.D Memorial Sloan Kettering Cancer Center
• Recipient of a $25,000 Close Family Research Award
• Abstract: 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 RRM2 as a new target for the treatment of liposarcoma.
• Final Report: Click to view PDF

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