Editorial

Three Research Grants Announced

We are proud to announce the funding of three new research studies: The role of CIP4 in osteosarcoma metastases; Small-molecule targeting of EWS-FLI1; and, Identification of the Ewing’s Sarcoma Stem Cell.

The role of CIP4 in osteosarcoma metastases

The Liddy Shriver Sarcoma Initiative and the FOSTER Foundation are co-funding a $50,000 research study, The role of CIP4 in osteosarcoma metastases, at the Children's Cancer Hospital at the University of Texas M.D. Anderson Cancer Center. Led by Nadezhda V. Koshkina, Ph.D., Assistant Professor, and involving Seth J. Corey, M.D. Professor of Pediatrics and Leukemia, this study is focused at expanding our knowledge of the metastatic mechanisms and identifying a new target for the treatment of osteosarcoma metastases. The following appears in the abstract of their grant application:

“The most common site of metastases for primary malignancies, including osteosarcoma (OS), is the lung. The best way to treat metastases would be to inhibit their spread at the earliest stage. Our long term goal is to evaluate the early mechanisms involved in the metastatic process in order to develop effective preventive metastases therapy. We recently identified the significant overexpression of CIP4 protein in the metastatic OS and breast cancer tumor cells compared with parental non-metastatic cells, which indicates on its potential role in metastases formation. Inactivation of CIP4 in breast cancer cells altered their metastatic phenotype in vitro. Our laboratory discovered CIP4 in a yeast two hybrid screen with a Src kinase as bait. CIP4 is a cytoskeletal scaffolding protein with an SH3 domain that binds N-WASP, which triggers actin polymerization. We believe that CIP4 regulates cytoskeletal assembly, which is essential for a variety of behaviors such as invasion and metastasis. However, very little is known about its role in cancer and until now the function of CIP4 was investigated only in vitro. Here we propose to investigate the role of CIP4 in OS metastases formation in vitro and in vivo.”

You can read more about the approach they are taking in this study in their article, Novel targets to treat osteosarcoma lung metastases, which appears in this issue of ESUN.

Small-molecule targeting of EWS-FLI1

The Liddy Shriver Sarcoma Initiative and the Amschwand Sarcoma Cancer Foundation are co-funding a $50,000 research study, Small-molecule targeting of EWS-FLI1, at the Lombardi Comprehensive Cancer Center at Georgetown University. The funding of this grant is also made possible by a generous gift from the Arlo and Susan Ellison family to the Liddy Shriver Sarcoma Initiative. Led by Jeffrey A. Toretsky, M.D. who is in the Departments of Oncology and Pediatrics and is the Co-director of the Pediatric Cancer Research Program, and involving Milton L. Brown, M.D., Ph.D., who is the Director of the Drug Discovery Program at Georgetown University Medical School, this study acts as a cornerstone upon which to base molecular therapy directed towards disrupting the relationship between EWS-FLI1 and RNA Helicase A to improve patient survival. The following appears in the abstract of the grant application:

“The Ewing’s Sarcoma Family of Tumors (ESFT) contains a characteristic translocation, t(11:22), which leads to the oncogenic transcription factor EWS-FLI1. We sought to dissect EWS-FLI1 induced tumorigenesis by identifying its critical protein partners. We identified RNA Helicase A (RHA, a.k.a. NDHII), a DEAD/H family member that modulates gene expression, as a critical partner of EWS-FLI1. Our data suggest that complex formation between EWS-FLI1 and RHA augments EWS-FLI1-mediated transcription and transformation. When RHA is specifically mutated to prevent EWS-FLI1 binding, there is no augmentation of soft-agar colony formation. Expression of the E9R peptide, that prevents EWS-FLI1 binding to RHA, eliminates ESFT soft agar colony formation, while other non-ESFT tumors are unaffected. Together, these findings suggest that RNA helicases interact with tumor-specific oncoproteins, such as EWS-FLI1, to modulate transformation. Using surface plasmon resonance (Biacore) screening, we have identified a series of small molecules that bind to EWS-FLI1. One of these small molecules has a significant structural homology to the E9R peptide and is our current lead compound. Since we hypothesize that the interaction of RHA with EWS-FLI1 results in a potent ESFT oncogenic transcriptional activator/coactivator complex, our efforts are focused on developing optimized lead compounds that block RHA binding to EWS-FLI1.”

You can read more about the approach they are taking in this study in Dr. Toretsky’s article, Small Molecules that can inhibit EWS-FL1 may represent novel and specific therapy for ESFT patients, which appears in this issue of ESUN.

Identification of the Ewing’s Sarcoma Stem Cell

The Liddy Shriver Sarcoma Initiative is funding a $37,800 research study, Identification of the Ewing’s Sarcoma Stem Cell, at the Sidney Kimmel Comprehensive Cancer Canter at Johns Hopkins Medical School. The funding of this grant is made possible by a generous gift from the Arlo and Susan Ellison family to the Liddy Shriver Sarcoma Initiative, by family and friends to honor the memory of Christie Campbell, Jeremy Zimmer, Brad Rice, Peter Skelton, and Paul Onvlee who all fell victim to this disease, and by family and friends to honor Teri Marriage, Matthew Beaver, and Nick Gibboni who are all still fighting it. Donations were also received in memory of Jeremy's grandfather, Robert Pickrell.

This study is led by David M. Loeb, M.D., Ph.D. who is Director of the Musculoskeletal Tumor Program and Co-Director of the Sarcoma Program. Dr. Loeb will be joined by Saul J. Sharkis, PhD, Professor of Oncology and Medicine, Chi Van Dang, M.D., Ph.D., Professor of Cell Biology and Jason T. Yustein, M.D., Ph.D., a fellow in the Pediatric Hematology-Oncology program. This team hopes to demonstrate the existence of Ewing’s sarcoma stem cells and then to begin the functional characterization of these cells. The following is taken from the abstract of the grant application:

“The cancer stem cell (CSC) model predicts that there is a small subpopulation of “stem cells” within each tumor that is responsible for tumor self-renewal, generation of the bulk of the tumor cells, and causing relapse. CSCs have been identified in brain tumors, breast cancer, and leukemia. It is not known whether Ewing’s sarcoma (EWS) stem cells exist. The aims of this proposal are 1) to demonstrate the existence of EWS stem cells (ESSC) and 2) to begin the functional characterization of these cells. We will use EWS cell lines, and these will be analyzed using 3 different assays, both singly and in combination: 1) exclusion of the DNA binding dye Hoechst 33342, 2) high level expression of aldehyde dehydrogenase, and 3) ability to form spherical colonies in nonadherent culture conditions. The combinatorial application of these assays to a single cell population is a novel approach that has not been reported before. We will also evaluate several EWS xenografts to confirm the presence of these cells in a second model system. Putative ESSCs will then be injected into immunodeficient mice to evaluate their tumorigenicity and self-renewal, the hallmarks of CSCs. Upon successful completion of this study, we will have demonstrated the existence of ESSCs in both EWS cell lines and in xenograft models and will have begun the initial functional characterization of these critical cells. Future work will then confirm that ESSCs are found in primary EWS samples, will perform more detailed analysis of the biology of these cells (including identification of the cell of origin of Ewing’s sarcoma and assessing the potential of ESSCs for differentiation), and will eventually lead to the development of therapies targeted at the cells that are responsible for disease relapse and patient death. Such therapies are expected to profoundly impact the course of EWS, especially for patients with metastatic disease at the time of diagnosis, whose prognosis has not changed over the past 40 years.”

You can read more about the approach they are taking in this study in Dr. Loeb’s article, Identification and Characterization of the Ewing’s Sarcoma Stem Cell, which appears in this issue of ESUN.

A Record of Collaboration

We are quite excited about partnering with the FOSTER Foundation to fund the research study The role of CIP4 in osteosarcoma metastases at M. D. Anderson Cancer Center and about partnering with the Amschwand Sarcoma Cancer Foundation to fund the research study Small-molecule targeting of EWS-FLI1 at the Lombardi Comprehensive Cancer Center. By combining our financial resources, our organizations can fund more substantive research studies jointly than we could fund independently. The Liddy Shriver Sarcoma Initiative has also co-funded research studies with the Brian Morden Foundation, LMSarcoma Direct Research Foundation (LMSdr), and Bone Cancer International and we have funded three Sarcoma Foundation of America (SFA) initiated research studies. The Liddy Shriver Sarcoma Initiative now funded fifteen research studies in sarcoma. This represents over $486,000 in research funding. We intend to continue to seek out other sarcoma advocacy groups to help fund research studies that have been recommended for funding as a result of our peer-reviewed grant application process having been completed. Working together we can make a difference. We hope that some of the results of these research studies will be stepping stones to finding a cure for sarcoma.

Best,

Bruce

Bruce D. Shriver, PhD

Editor-in-Chief, ESUN