Dr. Elizabeth Lawlor of the University of Michigan

Despite aggressive local control measures and systemic chemotherapy, over a quarter of patients with localized Ewing sarcoma family tumors (EFT) and nearly all patients with metastatic disease will relapse at distant sites following a period of initial clinical remission. Unfortunately, the outlook for these patients is dismal and novel approaches to therapy are desperately needed. One of the biggest impediments to improving outcomes and quality of life for patients with EFT is our inability to effectively identify and target the cells that initiate tumor metastasis. The studies outlined in this proposal aim to address these critical gaps in our knowledge.

In other tumors it has been shown that a protein called CXCR4, which is present on the surface of some tumor cells, responds to circulating factors and induces the tumor cell to invade surrounding tissues and travel to distant sites. Preliminary evidence from our lab and others suggests that some EFT cells express high levels of CXCR4 and that these cells may be the cells that initiate metastasis. Importantly, a new class of compounds that inhibits a key biologic pathway that is activated by CXCR4, the Rho-MKL pathway, has recently been described. In laboratory models these compounds have been shown to inhibit the invasion of other aggressive tumor types including melanoma and prostate cancer and early studies in our lab indicate that they may also be effective at inhibiting EFT cell invasion. In this proposal we will test the hypothesis that CXCR4 positive tumor cells and the Rho-MKL pathway are key mediators of EFT metastasis. In addition, we will test small molecule inhibitors of the RhoA-MKL pathway to evaluate their efficacy as potential novel agents for the prevention of EFT metastasis. It is our long-term goal, through these studies and others, to improve outcomes for patients with EFT by preventing metastatic relapse. .

Dr. Dean Lee of MD Anderson

For over 30 years natural killer cells (NK cells), one of the white blood cells of our immune system, have been known to kill many types of cancer cells, including those that occur in children such as AML, neuroblastoma, osteosarcoma, and Ewing's sarcoma. Different than T cells and B cells, which are trained to recognize special tumor-specific targets, NK cells require no special training. Under the right circumstances, cells in the body raise the alert level for NK cells, allowing them to recognize tumor cells or virus-infected cells on the basis of "danger" signals. Many new therapies, such as antibodies or immune modulating agents, work by increasing the danger signals recognized by NK cells, and therefore require NK cells in order to be effective. However, cancer often makes NK cells dysfunctional, and these cells are further damaged by chemotherapy. Recent studies have shown that healthy, functional NK cells can be safely transferred from a normal donor to a patient, but this approach is limited by the low numbers of NK cells that can be extracted from a donor, the cost of collecting NK cells, the cost and side effects of certain drugs (cytokines) needed to improve NK cell function, and the ability of cancers to escape being recognized by NK cells.

We recently developed a method to grow NK cells in the lab (increasing the numbers by 30,000-fold or more in 3 weeks), so that a small amount of blood from a donor can produce enough cells to deliver repeated large doses of NK cells in clinical trials. This system also dramatically raises the NK cell "alert level" to tumor targets. Our current project funded by the Sunbeam Foundation is to see whether we can grow large numbers of functional NK cells from patients with bone sarcomas, and to identify optimal immune modulating drugs that will make bone sarcomas express their "danger" signals so that they are even more likely to be killed by NK cells. We are working to combine these two approaches in first-in-human clinical trials with the hope of developing an effective, low-toxicity, immune therapy for bone cancers.

Dr. Alejandro Sweet-Cordero of Stanford University

Dr. Alejandro Sweet-Cordero is paving the way to find better treatments for Ewing’s sarcoma, the second most common type of bone cancer in children. After completing medical school and residency training at the University of California, San Francisco, Dr. Sweet-Cordero became a post-doctorate fellow at the Broad Institute and Massachusetts Institute of Technology Center for Cancer Research and Dana-Farber Cancer Institute. It is here that he conducted his initial studies on Ewing’s sarcoma. He is now continuing this work in his own independent laboratory at Stanford.

Dr. Sweet-Cordero’s laboratory is attempting to reproduce, in a mouse, the genetic abnormality seen in patients with Ewing’s sarcoma. By using genetic engineering techniques, they are developing mice with the abnormal chromosome translocation that is seen in children with the disease. The goal is to study how Ewing’s sarcoma develops in a living organism. For example, it is not known what type of cell in the body is the cell of origin for Ewing’s sarcoma. By activating the translocation in different tissues within the mouse, and observing which mice develop cancer, Dr. Sweet-Cordero hopes to be able to answer this question. Generating mice that have a Ewing’s sarcoma-like cancer will also allow him to test novel therapies for use in humans.

Dr. Scott C. Borinstein, Monroe Carell Jr. Children's Hospital at Vanderbilt

Dr. Scott C. Borinstein is the newest exciting addition to the Sunbeam team. He is an Assistant Professor in the Department of Pediatrics Division of Pediatric Hematology/Oncology at Vanderbuilt University. Dr Borinstein received his bachelor's degree from the University of Richmond followed by his MD and PhD from Medical College of Virginia at Virginia Commonwealth University. At Seattle Children’s Hospital, University of Washington, Dr. Borninstein conducted is residency program. From 2005-2008, he did a Fellowship in Pediatric Hematology/Oncology at Seattle Children’s Hospital at the University of Washington, Fred Hutchinson Cancer Research Center in Seattle Washington. In 2009 Dr. Bornstien became an assistant Professor, in the Department of Pediatrics, Division of Pediatric Hematology/Oncology, at Vanderbilt University where he is also the Director of the Pediatric Sarcoma Program. Dr. Bornstiens prolific young career and exciting and promising research is a wonderful addition to our family.

Dr. Borinstein's research focuses on the development of better treatment for pediatric sarcomas. Specifically, his laboratory investigates how changes in DNA methylation contribute to the pathogenesis of Ewing Sarcoma. DNA methylation is an epigenetic mechanism that contributes to the regulation of genes. His laboratory is trying to understand how DNA methylation contributes to Ewing Sarcoma tumor formation and spread and to determine if methylation of certain genes could play a role in diagnosis, treatment, or the development of novel treatments for this disease. The Sunbeam Foundation is extremely excited about Dr. Borinstein's research and we are proud to support him.

Dr. Stephen Lessnick, Huntsman Cancer Institue, University of Utah

Dr. Lessnick is an Assistant Professor of pediatrics, adjunct Assistant Professor of oncological sciences, and an investigator at the HCI Center for Children. Lessnick earned his bachelor's degree from Brandeis University followed by MD and PhD degrees from the University of California, Los Angeles (UCLA) as part of the Medical Scientist Training Program (MSTP). He conducted his internship and residency at Children's Hospital in Boston, followed by a fellowship in pediatrics hematology. He completed postdoctoral research in the Pediatric Oncology Department at the Dana-Farber Cancer Institute and joined HCI in January 2004.

Dr. Lessnick's Lab is interested in determining what genes are regulated by EWS/FLI (the key tumor-causing molecule in Ewing's Sarcoma), the role these genes play in the formation of Ewing's Sarcoma, and any other genetic alterations required for the genesis of Ewing's Sarcoma. To study these factors, Dr. Lessnick has developed model systems that allow the EWS/FLI to be turned on and off at will to determine which targets are altered and their roles in the development of Ewing's Sarcoma tumors. Through this process, Dr. Lessnick hopes to develop a complete understanding of the molecular basis of Ewing's Sarcoma and to apply this understanding to the treatment of patients with this devastating disease.