Grants Fund Two Research Studies Focusing on Ewing’s Sarcoma

Grants Fund Two Research Studies Focusing on Ewing’s Sarcoma

by Bruce Shriver, PhD

Director, Liddy Shriver Sarcoma Initiative

The Liddy Shriver Sarcoma Initiative is pleased to announce the funding of two research projects at the Huntsman Cancer Institute at the University of Utah. The two grants, totaling $50,000, are being made in memory of Liddy Shriver, Brian Morden, Krystle Smith, Shane Duffy, Conor O'Sullivan, Paul Onvlee, and Allen Strehlow and to honor those currently fighting this disease.

These grants were made possible because a number of people worked very hard in obtaining donations to sponsor much needed sarcoma research. Most of the donations were contributed in conjunction with the Team Sarcoma 2006 Initiative held earlier this year. We are extremely grateful to all of those involved in raising these funds, in particular, supporters of the Liddy Shriver Sarcoma Initiative, supporters of the Brain Morden Foundation, three Irish families — Patricia and Chris Smith, Joan Duffy, and William and Catherine Walsh, and three members of the Adult Bone Cancer Survivors support group — Mary Sorens, Rachel Baumgartner and Ashley Frost. We are also grateful to the family and friends of those who lost a loved one to Ewing’s sarcoma whose donations are helping sponsor these grants, in particular Maribeth Allen and Val Strehlow and Truus van der Spek. There is, as you can plainly see, strength in numbers.

Both of the studies will be directed by Stephen Lessnick, M.D., Ph.D. at the Huntsman Cancer Institute. The ultimate goal of the first study, "New Approaches for EWS/ETS Detection in Ewing’s Sarcoma" is to improve physicians’ abilities to provide an accurate diagnosis of Ewing’s sarcoma to patients, to provide physicians’ with molecular data which may be relevant to prognosis, and to provide a new non-invasive assay for the measurement of treatment response. The goal of the second study, "Analysis of NR0B1 in Ewing’s sarcoma" is to help to characterize the molecular mechanisms involved in Ewing’s sarcoma development. Additionally, by fully understanding these mechanisms, Dr. Lessnick and his team hope to identify new therapeutic approaches for patients with this devastating disease.

New Approaches for EWS/ETS Detection in Ewing’s Sarcoma

Ewing’s sarcomas are highly associated with recurrent chromosomal translocations. These translocations encode EWS/ETS fusion proteins. Detection of EWS/ETS fusions is a clinically-important adjunct in the diagnosis of patients with Ewing’s sarcoma. Unfortunately, the current technology for EWS/ETS detection is limited in sensitivity, and in some cases, specificity. A new methodology with improved characteristics could be used to assist in accurately diagnosing patients with Ewing’s sarcoma. Indeed, a highly sensitive and specific assay may be able to detect Ewing’s sarcoma cells in the blood and bone marrow of patients, thereby providing a new biomarker for Ewing’s sarcoma. This could result in diagnosing patients with Ewing’s sarcoma from a blood sample, in measuring their response to treatment, and in providing prognostic information to patients. Dr. Lessnick proposes to adapt a newly reported methodology, LMF, towards the detection of EWS/ETS fusion transcripts. He and his team will first develop the system to detect any of the various EWS/ETS fusion transcripts that have been reported. Next, they will assess the sensitivity and specificity of LMF on laboratory-based samples, and compare these results to the current gold standard, RT-PCR. Next, they will extend their analysis to determine if the methodology can be used to detect Ewing’s sarcoma cells in experimentally derived blood samples. Finally, they will assess this methodology to an animal model of Ewing’s sarcoma to mimic a likely clinical scenario. If they are able to successfully develop this assay, and if it is more sensitive and specific than the standard RT-PCR assay, they plan to further develop this into a clinical assay through ongoing collaborations with experts in the field of molecular testing for solid tumors. The ultimate goal of Dr. Lessnick and his team is to use this assay to improve physicians’ abilities to provide an accurate diagnosis to patients, to provide them with molecular data which may be relevant to prognosis, and to provide a new non-invasive assay for the measurement of treatment response.

Analysis of NR0B1 in Ewing’s sarcoma

Ewing’s sarcoma is a highly aggressive bone-associated tumor that is primarily diagnosed in adolescents and young adults. Most cases of Ewing’s sarcoma express a unique fusion oncoprotein, EWS/FLI. EWS/FLI functions as a transcription factor to dysregulate genes involved in cancer development. Because the cell of origin of Ewing’s sarcoma is unknown, prior work has studied the EWS/FLI fusion in heterologous cell types with uncertain relevance to the human disease. Dr. Lessnick and his colleagues recently developed a system to circumvent this difficulty. By "knocking-down" endogenous EWS/FLI expression in patient-derived Ewing’s sarcoma cell lines, using retroviral-mediated RNAi, they have been able to define the full complement of EWS/FLI gene targets in Ewing’s sarcoma. They have identified two of these as being critically important for tumorigenesis mediated by the fusion protein. One of these, NR0B1, is an orphan nuclear receptor whose only prior known role is in adrenal and sexual differentiation. Thus, they defined a new role for this factor.

Dr. Lessnick now proposes to characterize the structure-function relationships present in NR0B1. He and his team will use a "knock-down/rescue" system to remove endogenous NR0B1 expression, and replace it with mutant forms of the protein. In this way they will be able to determine which domains are important for the function of NR0B1 in tumor formation. These will serve as important preliminary data as we move forward to characterize the molecular mechanisms involved in Ewing’s sarcoma development. Additionally, by fully understanding these mechanisms, they hope to identify new therapeutic approaches for patients with this devastating disease.