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Funded Research The Liddy Shriver Sarcoma Initiative funds "basic research seed grants" in sarcoma. We anticipate that results from these “demonstration” or “starter” grants will provide results that will allow the researcher to apply for funding for a larger study. We are interested in a wide range of research. Some examples are: understanding the molecular biology of sarcomas; exploring “molecular targets” for new sarcoma therapies; studying chromosomal translocations, the oncogenes they generate and their role in sarcoma development; translational studies; studying vaccines, monoclonal antibodies, and mTOR inhibitors; studying the use of nanotechnology in the diagnosis and treatment of sarcomas; understanding the basis of radiation-induced sarcoma; modeling of the process of metastases; exploring the differences in the development of sarcomas in children, adolescents, young adults and adults; and research directed at the early detection and diagnosis of sarcoma. Other areas of research will be considered. For more details about our Research Grants initiative, click here.
We hope that some of the results of these research research studies that we have funded will be stepping stones to finding a cure for sarcoma.
The Liddy Shriver Sarcoma Initiative Awards Grant to Researchers at Tianjin Cancer Hospital in China and Institute and the University of Texas M.D. Anderson Cancer Center in Texas June 15, 2008: The Liddy Shriver Sarcoma Initiative is funding a $50,000 research study, Characterization of WWOX tumor suppressor gene in osteosarcoma, to researchers at Tianjin Cancer Hospital in China and Institute and the University of Texas M.D. Anderson Cancer Center in Texas. This study was made possible, in part, by several generous donations from Herbert Blodgett in loving memory of his wife, Merril, by donations from Una O'Hagen in memory of her son Sean Keane, donations from the Kleftis family in memory of Gregory. Led by Jilong Yang, M.D., Ph.D in China and his collaborator Wei Zhang, PhD, at M.D. Anderson Cancer Center, this study is focused on improving our understanding of the molecular mechanisms of osteosarcoma development by determining if the WWOX gene is a key tumor suppressor gene and a new target for gene therapy development for osteosarcoma. WWOX (WW domain containing oxidoreductase) is a tumor suppressor gene spanning a genomic region of 1.1 Mb located at chromosome 16q23.3-24.1, a region with a high incidence of loss of heterozygosity (LOH) in breast, lung, prostate, and other cancers. WWOX protein contains two WW domains in the NH2-terminal region and a short chain dehydrogenase/reductase (SDR) domain in the central region of the protein. Thus far, there is no information about WWOX gene in human osteosarcoma. Recently, Aqeilan et al generated a mouse strain with WWOX gene deleted and found spontaneously developed osteosarcoma in juvenile WWOX_/_ mice and lung papillary carcinoma in adult WWOX _/_ mice. In this study, we propose to test the hypothesis that the WWOX gene is an osteosarcoma tumor suppressor gene that is inactivated in human osteosarcoma. We will perform the following experiments in this study. 1. To examine homozygous deletion, loss of heterogeneity (LOH), methylation of WWOX promoter, and mutation of WWOX in osteosarcoma cell lines and patient tumor tissues. 2. To investigate the role of WWOX in cell apoptosis and proliferation by correlating WWOX gene deletion, mutation, and expression status with expression for P73, BAX, Bcl-2, Bcl-xL, casepase-3, casepase-9, Ki-67 and PCNA. We will use standard molecular and pathological methods including PCR analysis, sequencing, Immunoblotting and immunohistochemistry, methylation-specific PCR (MSP), DHPLC and flow cytometric analysis. The tissue bank of our hospital has accumulated 35 frozen osteosarcoma tissues and there are about 150 paraffin-embedded archival blocks available for this investigation. Our preliminary investigations in human osteosarcoma tissues detected WWOX gene deletion and promoter methylation. These studies support our hypothesis. You can read more about the approach they are taking in the article, Characterization of WWOX tumor suppressor gene in osteosarcoma, which appears in the June 2008 issue of ESUN.
The Liddy Shriver Sarcoma Initiative and the FOSTER Foundation Award Grant to Researchers at the University of Texas M.D. Anderson Cancer Center February 15, 2008. 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 the February 2008 issue of ESUN.
The Liddy Shriver Sarcoma Initiative and the Amschwand Sarcoma Cancer Foundation Award Grant to Researchers at the Lombardi Comprehensive Cancer Center at Georgetown University February 15, 2008. 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 the February 2008 issue of ESUN.
The Liddy Shriver Sarcoma Initiative Awards Grant to Researchers at Sidney Kimmel Comprehensive Cancer Canter at Johns Hopkins Medical School February 15, 2008. 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 the February 2008 issue of ESUN.
The Liddy Shriver Sarcoma Initiative and the Leiomyosarcoma Direct Research Foundation Award Grant to Researcher at New York University School of Medicine (NYU Press Release) New York, June 15, 2007 - Eva Hernando, PhD of the Department of Pathology at the NYU School of Medicine and her team have received a $50,000 year long grant from the Liddy Shriver Sarcoma Initiative and the Leiomyosarcoma Direct Research Foundation. The project is titled, "MicroRNA Deregulation in Mesenchymal Transformation and Sarcoma-genesis." The specific sarcoma under investigation is leiomyosarcoma. This project represents to our knowledge the first attempt to classify sarcomas based on their microRNA expression, and to explore the contribution of these small RNAs to sarcoma-genesis. We hope our research will lead to a better understanding of the pathogenesis of leiomyosarcoma and will unravel new potential targets for future therapeutic intervention,” commented Dr. Hernando, Assistant Professor of Pathology. The enormous clinical relevance of microRNAs was acknowledged by the 2006 Nobel Prize in Physiology or Medicine awarded to Fire and Melow, the two scientists who first discovered a new mechanism of genetic regulation mediated by these small RNAs. Sarcoma is a cancer of the connective tissues, including nerves, muscles, joints, bones, and blood vessels. It is a rare and dangerous cancer in adults, accounting for only 1% of all adult cancers, however it accounts for 20% of all childhood cancers. The word sarcoma is derived from the Greek “sarc” (fleshy) and “oma” (tumor). Sarcomas come in two types, soft tissue and bone/cartilage. Leiomyosarcomas account for about 7% of all soft tissue tumors. The word Leiomyosarcoma literally means smooth muscle fleshy tumor. Bruce and Beverly Shriver, who lost their daughter Liddy to Ewing’s sarcoma said, “We are delighted to be co-funding this grant with the Leiomyosarcoma Direct Research Foundation. We think that such collaborative efforts are very important as they offer small sarcoma advocacy groups like ours the opportunity to fund larger projects together than we could fund separately.” Suzanne Kurtz, a leiomyosarcoma patient herself, and her husband Ed were motivated to form the Leiomyosarcoma Direct Research Foundation in order to advocate for and fund more research on this rare disease. Suzanne says, with great passion, “We want to help keep many leiomyosarcoma patients alive until a cure is found!” The Shrivers added, “Dr. Hernando and her team are challenging conventional wisdom about how sarcomas originate. Their approach might result in a blueprint for similar studies in other types of sarcomas and thus benefit many other patients.” Clicking here to read more detailed information about this grant.
Liddy Shriver Sarcoma Initiative Grant Funds Chordoma Research Study at the Fondazione IRCCS Istituto dei Tumori in Milan, Italy April, 2007: The Liddy Shriver Sarcoma Initiative is pleased to announce the funding of a research project being undertaken by Dr. Silvana Pilotti in the Laboratory of Experimental Molecular Pathology of the Department of Pathology at the Fondazione IRCCS Istituto dei Tumori in Milan, Italy. The $25,000 grant is being made through the generosity of Stephen, Sally, and Eric Norcross in loving memory of Alison Norcross and through the generosity of Katherine Stadler and the former Bone Cancer International organization. The research study, "New methodological approaches in assessing and monitoring the targeted treatment of chordoma", will begin shortly. Chordoma is a very rare sarcoma. Dr. Pilotti told us that they have an incidence estimated around 1/1,000,000. She went on to say, "They originate from remnants of the fetal notochord and mainly affect the sacrum, skull base region and, in a minority of cases, the cervical and thoraco-lumbar vertebrae. Their localization makes the treatment of primary disease highly challenging in most cases. Surgery, the standard treatment, is often not effective in curing the disease. For this reason local relapse is common and affects the prognosis of most chordoma patients in the long run." The aims of the research study are to (a) monitor, through an innovative methodology (flow cytometry applied to solid tumors), the imatinib pharmacological response in patients during the treatment and (b) verify, through short term cultures or chordoma cell lines, the efficacy of new RTK inhibitors alone or in combination with DNA damaging agents, in order to find a second line therapy for patients who develop a resistance to imatinib, a phenomenon already observed in some patients. You can read more about this study by clicking here.
Grants Fund Two Research Studies Focusing on Ewing’s Sarcoma December 2006 — 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. 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. 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. You can read more about both of these grants by clicking here.
Grant to fund study of tissue samples in conjunction with a Phase II Trial of Dasatinib in Patients with Advanced Sarcoma at the University of Michigan’s School of Medicine
October 2006
—
The Liddy Shriver
Sarcoma Initiative is proud to announce that it has just awarded a grant of
$25,000 to help fund a SARC research study in which leiomyosarcoma,
liposarcoma, MFH, malignant peripheral nerve sheath tumor, rhabdomyosarcoma
and osteosarcoma patients will be eligible to participate. Dr. Scott
Schuetze of the Department of Internal Medicine at the University of
Michigan’s School of Medicine, who is heading up the study, said that
patients with alveolar soft part sarcoma, epithelioid sarcoma,
chondrosarcoma, hemangiopericytoma, giant cell tumor of bone and chordoma
will also be eligible to participate in the this study. Tumor samples
Grants to fund GIST Research in Germany and the United States October 2006 — The Liddy Shriver Sarcoma Initiative is proud to announce that two grants of $5,000 each (totaling $10,000) have been awarded to help fund gastrointestinal stromal tumor (GIST) research in the laboratory of Dr. Sebastian Bauer at the West German Cancer Center at the University Hospital in Essen, Germany and at the laboratory of Dr. Anette Duensing at the Hillman Cancer Center at the University of Pittsburgh Cancer Institute. We are indebted to GIST Support International for the central role they played in helping fund this research study. Click here to read more details about these grants.
Cancer Vaccine Study at the Dana-Farber Cancer Institute September 2005 — The Liddy Shriver Sarcoma Initiative donated $50,000 to Dana-Farber Cancer Institute to support a vaccine study for clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS), and pediatric melanoma. Dr. John Goldberg and Dr. David Fisher are co-directing this study. The vaccine trial for CCS, ASPS and pediatric melanoma should become fully activated and available for patients in the next 4-6 weeks. Links to find out more information, including who will be eligible and whom to contact for enrollment, will be available when it becomes fully active through links on the ESUN, the NCI, the DFCI and TAAASPS. Patients who are eligible for the study and who consent for the trial will undergo an operation in Boston to remove their own tumor tissue, from which the vaccine will be made. The tumor will be brought to a special laboratory and have a gene for GM-CSF, a powerful cytokine that stimulates the immune system, added to the individual tumor cells. The tumor cells will then be irradiated so that they can never grow again and tested to make sure they make GM-CSF. The cells will then be frozen for safe keeping while the patient recovers from surgery. If this process works correctly, the vaccine cells will then be given back to the patient in weekly and then bi-weekly injections over the course of several months. For additional information, see the press release.
Developing a Vaccine for Treating SarcomaJanuary 2005 — The Brian Morden Foundation and the Liddy Shriver Sarcoma Initiative have joined forces to fund $50,000 for research on a vaccine to treat recurrent and relapsed Ewing's Sarcoma, a rare cancer. The vaccine is being developed by a team of oncology specialists at the University of Michigan Medical Center led by Dr. James Geiger, with Dr. John E. Levine and Dr. Raymond Hutchinson as co-investigators. This study continues an initial Phase I Clinical Trial funded by the National Institutes of Health that Dr. Geiger and his team initiated. Funds from the Brian Morden Foundation and the Liddy Shriver Sarcoma Initiative, in addition to grants from the University of Michigan will allow doctors to offer a new alternative to patients whose traditional chemotherapy and radiotherapy have failed. For more details, click here and also see the press release.
Three Elizabeth Shriver Memorial Research Awards to Study Sarcoma June 2004 — The Sarcoma Foundation of America announced its annual research awards. Among them were three grants we funded totaling $75,000. See the press release for additional information.
Dr. Matt van de Rijn of Stanford University is the recipient of a $25,000 Elizabeth Shriver Memorial Research Award. He is one of the few researchers in the country to use gene chips on sarcomas. He will use the sarcoma cell lines generated by Dr. Fletcher to analyze thousands of genes in these tumors. The technique is called DNA microarray and allows one to put the tumor DNA on a chip containing DNA from essentially all known genes; if the tumor DNA binds, it means that gene is present in the tumor. One can then tell if key genes in the tumor are absent (allowing the tumor to grow unchecked) or abnormal. Once these abnormal genes are found, researchers can attempt to block their effect using various molecules — thus searching for so-called "molecular targets" for new therapies. "Again, the Sarcoma Foundation of America and the Elizabeth Shriver Award will have a significant impact on our knowledge of how sarcomas grow, and on future sarcoma research," Thornton said. “This is the type of study that can lay the groundwork to find the magic bullet, though it will likely take years.”
Dr. Frederic Barr of the University of Pennsylvania is also the recipient of a $25,000 Elizabeth Shriver Memorial Research Award. He is well known for his work on gene fusions in rhabdomyosarcoma (RMS), so he is well familiar with the complex genes in this tumor. Most of the alveolar type of RMS, a childhood tumor, form when two genes are abnormally stuck together (PAX and FKHR genes). For unknown reasons, some alveolar RMS lack this finding and yet still form and grow. “In this grant, Dr. Barr will try to determine how and why some rhabdomyosarcomas do not have the usual gene fusion, which causes abnormal growth,” explained Thornton. “Perhaps by learning this, some mysteries of RMS can be unraveled. Often by testing the exceptions to the rule one can learn a great deal and perhaps find another molecular target.”
Dr. Lisa Wang of Baylor College of Medicine in Houston is also the recipient of a $25,000 Elizabeth Shriver Memorial Research Award. She had been involved in studying a group of people with a genetic syndrome that results in a certain germ-line mutation in all their normal cells. The gene, called RECQL4, is a DNA helicase (enzyme) that functions to maintain genomic stability. When it is mutated there is genetic instability and an increased risk of osteosarcoma. She will now test whether or not the same mutations are a common feature of all osteosarcomas. If this gene is very common in osteosarcomas, it may then become a target for therapy in the future. "It is possible that this rare genetic syndrome may lead to finding a key gene in this bone tumor, and the Sarcoma Foundation of America and Elizabeth Shriver Award is critical to getting this investigation done and an answer known. Only by following such leads is progress made," said Thornton.
Our First Research Grant As a results of or first Team Sarcoma's participation in Cycle Zydeco 2003, we raised $14,000 to sponsor the research of Dr. Mary Louise Keohan at the Herbert Irving Comprehensive Cancer Center at Columbia University and the New York Presbyterian Hospital.
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