Most cancers arise from the epithelium, the tissue that lines the body and the organs, but sarcomas arise from connective tissue cells, like the bones. At Georgetown Lombardi Comprehensive Cancer Center, research have engaged in full swing to develop new therapies to treat osteosarcoma and Ewing's sarcoma, the two most common bone tumors in children, adolescents and young adults.
At the AACR 101st Annual Meeting 2010, they offer new molecular insights into the translocation that causes Ewing's sarcoma, a genetic exchange between chromosomes that results in a fused gene that produces an oncogenic protein. These findings, coupled with use of sophisticated drug design technology, have led to identification of three new targets for potential treatment of this rare cancer. Additionally, researchers have identified two small molecules that have the potential to prevent or treat spread of osteosarcoma, a very aggressive cancer. (Embargoes listed with each abstract summary that follows).
"Scientific studies in the past decade identified very promising molecular targets that play a major role in tumor progression and invasion. With the help of a multidisciplinary team of scientists at Lombardi, we are now focusing on developing small molecules that can hit these targets," says Aykut Üren, M.D., assistant professor in the Department of Oncology at Lombardi. "With this truly translational experimental approach, we may be able to optimize our small molecules for clinical trials in the near future."
Targeting of EWS-FLI1 with small molecule YK-4-279 reduces xenograft growth by disruption of disordered protein-protein interactions (abstract #3411)
EMBARGO: Tuesday, April 20, 2010, 9:00 am ET
Author's summary: "Because the oncoprotein that causes the Ewing's sarcoma is so disordered, we reasoned that it might be possible to use a small molecule to target that protein and disrupt a key protein-protein interaction, leading to decreased cancer growth. Using state-of-the art tools, we screened 3000 compounds and found one, YK-4-279, that significantly inhibited this protein-protein binding. We have now demonstrated that YK-4-279 has a detrimental effect on Ewing's sarcoma both in vitro and in vivo, providing us with an oncogenic target and a lead compound for therapeutic testing." -Jeffrey ToretskyAuthors: Jeffrey A. Toretsky, Hayriye V. Erkizan, Yali Kong, Julie S. Barber-Rotenberg, Milton L. Brown, and Aykut Üren, of Georgetown Lombardi Comprehensive Cancer Center; Melinda Merchant, of Pediatric Oncology Branch, National Institutes of HealthTo be presented: Tuesday, April 20, 9:00 am -12:00 pm; Exhibit Hall A-C, Poster Section 18; Board 12
EWS-FLI1 is regulated by acetylation(Abstract # 3897)
EMBARGO: Tuesday, April 20, 2010; 2:00 pm ET
Author's summary: "EWS-FLI1 is a protein specific to Ewing's Sarcoma Family of Tumors (ESFT). EWS-FLI1 is a transcription factor and thereby a central regulator of ESFT cell survival and tumor growth. The mechanisms controlling its function and stability are not well understood. We show, for the first time, that EWS-FLI1 is modified by acetylation, a process that can in fact regulate both stability and function of proteins. Drugs called Histone Deacetylase Inhibitors (HDI) inhibit the reverse process, the deacetylation of proteins, and are promising in the treatment of a variety of cancers. HDI act mainly (but not solely) by deacetylating histone protein, and are very active in inducing cell death of ESFT cells. We investigate how acetylation regulates EWS-FLI1 and the possibility of EWS-FLI1 being a specific target for the activity of HDI in ESFT cells." -Silke SchlottmannAuthors: Silke Schlottmann, Hayriye V. Erkizan, Julie Barber-Rotenberg, Aykut Uren, Maria L. Avantaggiati, and Jeffrey A. Toretsky. Georgetown Lombardi Comp. Cancer Ctr., Washington, DC.To be presented: Tuesday, April 20, 2:00 - 5:00 pm; Exhibit Hall A-C, Poster Section 2; Board 5
Arsenic trioxide inhibits Ewing sarcoma growth by blocking Hedgehog/GLI pathway (Abstract # 3409)
EMBARGO: Tuesday, April 20, 2010; 9:00 am ET
Author's summary: "The protein GLI1 is important for the growth of many cancers such as pancreatic and brain tumors. We have previously published that the protein GLI1 is important for the growth of Ewing Sarcoma. We show data that an already FDA approved drug Arsenic Trioxide which is used to treat a specific type of leukemia can inhibit the protein GLI1. Arsenic Trioxide can inhibit the growth of a specific type of pediatric brain cancer called Medulloblastoma as well as Ewing sarcoma in mice. Therefore Arsenic Trioxide can be investigated in clinical trials to treat Ewing Sarcoma as well as other types of cancers that depend on hyperactivity of the protein GLI1." - Elspeth M. BeauchampAuthors: Elspeth M. Beauchamp, Olga Rodriguez, Christopher Albanese, Jeffrey A. Toretsky, and Aykut Üren, from. Georgetown Lombardi Comp. Cancer Ctr., Washington, DCBeauchampTo be presented: Tuesday, April 20, 9:00 am - 12:00 pm ET, Exhibit Hall A-C, Poster Section 18, Board 10
EWS-FLI1 as a molecular target: Small molecule inhibitors for a disordered protein (Abstract #2681)
EMBARGO: Monday, April 19, 2010; 2:00 pm ET
Author's summary: "Ewing's sarcoma family of tumors are characterized by the EWS-FLI1 oncogenic fusion protein. Previous studies show that RNA Helicase A (RHA) binds with EWS-FLI1 to enhances the oncogensis of EWS-FLI1 and the interaction between these two proteins can be disrupted by small molecule inhibitors. To test analogues of the lead small molecule, a biophysical assay is necessary to determine binding. AlphaScreen technology allows for a peptide displacement assay to study binding in a 96 well plate format, requiring minimal reagents and a higher-throughput format. Data from binding studies will help to predict and direct the design of more potent analogues." - Julie S. Barber-Rotenberg
Authors: Julie S. Barber-Rotenberg, Yali Kong, Nilan Schnure, Sivanesan Dakshanamurthy, Milton L. Brown, Hayriye V. Erkizan, Aykut Uren. and Jeffrey A. Toretsky, from Georgetown Lombardi Comprehensive Cancer Center; Peter Frazier, Cornell UniversityTo be presented: Monday, April 19, 2:00 pm - 5:00 pm; Exhibit Hall A-C, Poster Section 28; Board 14
Phage display identifies novel toxic binding peptides for the disordered oncoprotein EWS-FLI1(Abstract #3412)
EMBARGO: Tuesday, April 20, 2010, 9 AM
Author's summary: "The EWS-FLI1 protein results from a tumor-specific chromosomal translocation and is uniquely expressed in Ewing's Sarcoma Family Tumors (ESFT). EWS-FLI1 is a disordered protein and thus presents opportunities for manipulating protein-protein interactions, some of which will be specific anti-tumor targets. By looking at and identifying various peptides and their cognate proteins, we can investigate the function of EWS-FLI1 in order to improve therapies for ESFT patients. The A1 peptide, which we focused on specifically, appears to directly bind to the EWS-FLI1 protein and lead to cell death in cells with the EWS-FLI1 fusion protein." - Lauren M. JacobwitzAuthors: Lauren M. Jacobwitz, Hayriye V. Erkizan, Aykut Üren, and Jeffrey A. Toretsky, Georgetown Lombardi Comprehensive Cancer CenterTo be presented: Tuesday, April 20, 9:00 am - 12:00 pm ET; Exhibit Hall A-C, Poster Section 18; Board 13
Small molecule inhibitors of ezrin as anti-metastatic agents in osteosarcoma (Abstract #1550)
EMBARGO: Monday, April 19, 2010; 9:00 am ET
Author's summary: "Our study is focused on developing new therapies for osteosarcoma (OS). OS is a very aggressive cancer of the bone. Death from OS is generally results from respiratory failure due to spread of cancer to the lungs. Ezrin is a protein in the cell that contributes to the biology of cancer, especially to its growth and spread to other body parts. Accumulating evidence from experimental animal models and human cases suggest that ezrin is a key factor in spread of OS cells. Here we report the discovery of two lead compounds that directly bind to ezrin protein and inhibit its function in multiple assays. These small molecules have the potential to prevent or treat OS spreading to the lungs and significantly improve survival of OS patients." - Gülay BulutAuthors: Gülay Bulut, Kevin Chen, Eric Glasgow, Jeffrey A. Toretsky, and Aykut Üren, Georgetown Lombardi Comprehensive Cancer Center; Sung-Hyeok Hong, Chand Khanna, Hyun-Shik Lee, and Ira Daar, National Cancer Institute.To be presented: Monday, April 19, 2010 9:00 am - 12:00 pm ET; Exhibit Hall A-C, Poster Section 23; Board 3