About Ewing Sarcoma
Ewing sarcoma survival rates have reached a plateau in recent decades – overall the five-year survival rate is just 60%. Survival rates for patients with metastatic disease or who relapse are much lower. This plateau suggests that conventional treatment regimens have reached the limit of their efficacy and underscores the need to develop new or improved therapies. Development of such therapies might also avoid or mitigate the adverse side effects of conventional chemotherapy.
The Nick Currey Fund is currently supporting a number of research projects aimed at improving outcomes for children diagnosed with Ewing sarcoma.
Andrew Kung, MD, PhD
Chair of the Department of Pediatrics
Memorial Sloan Kettering
The Nick Currey Fund supported a portion of the almost $1.3 million grant awarded as part of CureSearch's "Acceleration Initiative" to fund an innovative project led by Dr. Andrew Kung, Chair of the Department of Pediatrics at Memorial Sloane Kettering, in New York City. Dr. Kung's team developed a new method to assess the entire signaling network within cancer cells, and to identify the critical signaling nodes, or Master Regulators (MRs), that drive malignancy.
The team used a systems biology approach, where molecular profiling is paired with bioinformatics to identify the key MRs. They have successfully used this method to identify critical MRs in a number of adult cancers. Using this approach, they analyzed single patient samples from children with high-risk sarcomas and identified MRs and then identified drugs that target the activity of the MRs.
(Spring 2022 Update) Dr. Kung’s team has identified a pediatric Master Regulator (MR)-targeting therapy with significant efficacy in cell and animal models of Wilms tumor and rhabdoid tumor. There are new drugs that specifically impact the identified target Exportin 1, with the first-in-class drug, Selinexor, now FDA approved for use in multiple myeloma. Dr. Kung and his team will be enrolling patients in the next few months and are in the process of opening the trial at other national sites. Additionally, a manuscript describing these studies, along with a patient treated with Selinexor on a compassionate use basis, is currently under review.
Mary Beckerle, PhD
Ralph E. and Willia T. Main Presidential Professor
CEO and Director, Huntsman Cancer Institute
The University of Utah
Ewing sarcoma occurs because of a chromosomal abnormality that causes an atypical protein, known as EWS/FLI, to be expressed. Dr.Beckerle and a collaborative team at the Huntsman Cancer Institute have demonstrated that the EWS/FLI mutation disrupts the internal cellular skeleton, which allows cells to move out of their normal environment. A cell that does not remain in its normal environment is more likely to travel to another area of the body, facilitating the spread of the tumor. Therefore, being able to stop EWS/FLI from changing a cell’s “stickiness” might help stop the spread of cancer. Dr. Beckerle’s team identified a novel targeted treatment for Ewing sarcoma that disrupts the effects of EWS/FLI and disrupts the spread of the cancer. Dr. Beckerle’s Acceleration Award contributed to the clinical studies required to move this novel therapy into clinical trials.
As of the conclusion of her CureSearch-funded project, Dr. Beckerle has supported the movement of a new therapeutic for Ewing sarcoma into the clinic:
- 1 Phase I clinical trial initiated for Ewing sarcoma based on data obtained during the award period
- 1 new metastatic Ewing sarcoma mouse model created
- 1 novel drug carried through preclinical testing and licensed to Salarius Pharmaceuticals
- 1 IND application filed for drug assessed during CureSearch funding
Additionally, the novel drug licensed to Salarius Pharmaceuticals will be used in a 2022-2025 CureSearch-funded project. Click here to learn more.
Stephen Lessnick, MD, PhD
Jon and Karen Huntsman Presidential Professor in Cancer Research
Director, Center for Children's Cancer Research at Huntsman Cancer Institute
University of Utah
Julia Bridge, MD
Professor, Pathology, Pediatrics, and Orthopedic Surgery
Associate Director, Clinical Cytogenetics
Director, Sarcoma Rearrangement Testing for Molecular Diagnostics
University of Nebraska Medical Center
Based on data suggesting that alterations in two specific genes, p53 and pl6, may help predict future outcomes for patients with Ewing sarcoma, Drs. Stephen Lessnick and Julia Bridge are evaluating how often 2 specific genes are altered in a large cohort of tumor specimens, and whether these alterations predict patient outcomes. As part of the study, the investigators will also "amplify" tumor DNA to allow them to study the genes and create an important resource for other investigators studying this disease. If this study supports the idea that p53 and/or pl6 alterations can predict patient outcome, these tests might then be incorporated in future clinical trials for patients with Ewing sarcoma.
Elizabeth Lawlor, MD
Russell G. Adderley Professor of Pediatric Oncology
Associate Professor, Pediatrics and Pathology
University of Michigan
Dr. Lawlor's lab previously identified that Ewing sarcoma cells survive when deprived of oxygen. Dr. Lawlor and colleagues discovered that suppression of the potassium ion channel Kv1.5 is, at least in part, responsible for this abnormal cell survival. Kv1.5 is a type of protein in cells that moves potassium out of cells. Therefore, Dr. Lawlor hypothesizes that restoring expression of the Kv1.5 channel in Ewing sarcoma cells may inhibit their resistance to cell death and lead to better outcomes for patients. Dr. Lawlor and her team will study both normal and cancer cells to understand Kv1.5 channel suppression in Ewing sarcoma. Cell death under conditions of stress requires potassium ions move out of the cell, which is often blocked in cancer, leading to abnormal cell survival. Understanding how this response is disrupted in Ewing sarcoma can lead to tools to reactivate it and ultimately prevent survival of the most therapy-resistant cells and thereby prevent tumor relapse.
Joshua Schiffman, MD
Division of Pediatric Hematology/Oncology
University of Utah
Using microarray technology, Dr. Schiffman and his colleagues retrospectively examined archived tissue samples from 40 patients at the University of Utah, including tissue from patients who had both relapsed and metastatic disease. A gene called CEBPB was found to be amplified in many patients - instead of the normal two copies of the chromosome, there were as many as 11. Further research identified seven other chromosomal regions in Ewing sarcoma patients in which amplification or missing genes occurred. Those with changes in gene copy numbers are called Multifactor Copy Number (MCN)-positive and those without changes are called MCN-negative. In comparing the findings to the patients' clinical outcomes it was found that patients who were MCN-negative had a 100% survival rate over 12 years, compared to a 41% survival rate over 12 years for those patients who were MCN-positive.
The study is being expanded to examine tissue samples from across the country and determine if findings can be validated. If they are, it may lead to a change in protocol treatment for patients with Ewing sarcoma as tumors could be examined at diagnosis and therapy adjusted based on the MCN status of individual patient tumors.
Jeffrey Toretsky, MD
Lombardi Comprehensive Cancer Center
In a study conducted at Georgetown University's Lombardi Comprehensive Cancer Center, a small molecule drug specific to Ewing Sarcoma was researched. The project looked at how combinations of a drug specific to Ewing Sarcoma, YK-4-279, and current cancer therapies interact synergistically. The findings from the study will help inform how the drug may be used as a therapy. Furthermore, the study may help define how YK-4-279 works inside Ewing sarcoma cells.
Bringing together data from multiple Ewing sarcoma studies with the hopes of funding overarching information to develop targeted treatments, the Nick Currey Fund is funding statisticians working on five projects.
- Expert pathologists have examined tumor tissue from hundreds of patients enrolled in clinical trials in the last two decades and are linking this data to the clinical outcomes of patients to determine if any particular features are related to outcomes.
- Assembling data from three studies of newly-diagnosed patients with Ewing sarcoma, statisticians are trying to determine not only if the age of diagnosis, race, and gender affect treatment outcomes and side effects, but also if interrelationships between these and other established factors increase risk of disease progression.
- The statistician is integrating data from a series of trials and conducting analyses to examine the effects of various surgical characteristics on disease outcomes and complications of surgery.
- The presence of EWS-FLi1 in blood and bone marrow samples is believed to serve as a marker for recurrence of Ewing sarcoma. To test this hypothesis, serial blood and bone marrow specimens from patients enrolled in a specific COG study were analyzed at the National Cancer Institute. Those results will be integrated into the dataset of another study to determine their prognostic significance.
- Statisticians are assembling and analyzing treatment and complication data related to rare tumor sites in Ewing sarcoma patients, such as the spine and skull. This information will be published and serve as a treatment guide for clinicians who are often presented with these rare cases only once or twice in their entire careers.