Ewing Sarcoma Research Foundation

What is Ewing Sarcoma?

Overview

Ewing Sarcoma was first described by Dr. James Ewing as a bone tumor distinct from osteosarcoma. It is now part of a family of tumors know as Ewing Family Tumors (EFT). These consist of Ewing sarcoma of bone, extraosseous Ewing tumor and peripheral primitive neuroectodermal tumor which can present in either bone or soft tissue (Anderson ME, et. al., 2014). They are considered as a family of tumours as they share similar DNA abnormalities.

Ewing sarcoma is arare but aggressive neoplasm of the bone and soft tissues. This cancer most often begins in the long bones of the pelvis, legs or arms, but it can occur in any bone. Ewing sarcoma affects children and young adults; it rarely occurs after the age of 30. Despite continuous therapeutic improvements, 5-year survival rates are not great in patients with advanced Ewing sarcoma.

How common is Ewing sarcoma?

Ewing sarcoma is the second most common type of bone cancer in children, but it is rare. About 200 children and young adults develop Ewing sarcoma each year in the United States.

What causes Ewing sarcoma?

The most common cause of Ewing sarcoma involves two genes, the EWSR1 gene on chromosome 22 and the FLI1 gene on chromosome 11. A rare genomic rearrangement (translocation) of genetic material between chromosomes 22 and 11, fuses part of the EWSR1 gene with part of the FLI1 gene, creating the EWSR1/FLI1 fusion gene (Fig. 3). The EWSR1/FLI1 protein controls the abnormal expression of a variety of genes. This dysregulation leads to uncontrolled growth, abnormal maturation and survival of cells, causing tumor development.

No known risk factors exist for the development of Ewing sarcoma, but it occurs more commonly in males in their teens and is more common among Caucasians compared to Asian Americans or African Americans.

Presenting symptoms can include pain and/or a mass. Systemic symptoms such as fever or weight loss may be present. Workup for Ewing sarcoma can include plain x-rays of the affected site, CT scan of the affected site and the lungs, and MRI scan of the affected site (DeLaney et. al., 2018). Bone scans and PET scan can be done to rule out distant disease. In some circumstances, a bone marrow biopsy may be performed to look for Ewing cells. Complete blood counts and blood chemistry tests can be performed, but no specific blood marker exist for Ewing’s.

Diagnosis of the disease is done by biopsy which typically reveals a malignant small blue round cell under the microscope. Additional testing with cytogentetics or fluorescent in situ hybridization (FISH) technology can confirm the translocation.

Treatment for EFT is done by a team of physicians with a combination of modalities. Chemotherapy is considered part of the standard for treatment, and surgery and/or radiation are used to achieve local control at the primary site.

Overall 5 year survival rate for EFT when it is localized is approximately 70%. The 5 year survival rate for patients who present with metastatic disease is in the 30% range. Patients whose metastatic disease is confined to the lung have a somewhat better prognosis.

At Cedars-Sinai, we have a multi-disciplinary team including medical and pediatric oncologists, dedicated musculoskeletal radiologist and radiation oncologists, and orthopedic and surgical oncologists to deal with Ewing sarcoma patients. In addition, our cases are presented at a tumor board which represents all these specialties and is overseen by dedicated, experienced sarcoma pathologists. Both pediatric and adult medical oncologists participate in the Children’s Oncology Group which allows access to current clinical trials. Charles Forscher (clinical oncologist) (Charles.Forscher@cshs.org; 310-423-8030) is the leader of the group with at least 20 years of experience.

Basic scientific research on Ewing sarcoma in Dr Koeffler’s lab at Cedars-Sinai Medical Center

Although EWSR1/FLI1 initiates and drives this malignancy. To silence this abnormal gene is extremely difficult by current pharmacologic approaches. Therefore, an urgent need exists to identify more effective and innovative therapeutic targets for Ewing Sarcoma, which can only be achieved through basic scientific research to understand the molecular mechanisms underlying the cell biology of Ewing sarcoma.

Dr. Koeffler’s lab has two main research foci as outlined below:

Discovery of potential drug targets in Ewing sarcoma: The lab is utilizing cutting-edge high-throughput technologies to screen for candidate “druggable” targets in Ewing sarcoma. Especially, with the help of robotics, the researchers are able to screen thousands of chemicals. Some of the recent results identified a protein which is capable of transporting cargos into and out of the nucleus of the cell, called CRM1. It is required for cell survival of Ewing sarcoma (Sun, Lin et al. 2016). Very recently, another protein SYK, which was also discovered by a similar approach, was found to a confer growth advantage to Ewing sarcoma cells (Sun, Lin et al. 2017). Notably, drugs that suppress CRM1 and SYK are under evaluation in clinical trials for patients with other cancer types. If these clinical trials are promising, these drugs may also offer clinical benefits for Ewing sarcoma patients.
Identify and study the important partners of EWSR1/FLI1 in Ewing sarcoma: Because EWSR1/FLI1 itself is very difficult to be inhibited by current pharmacologic approaches, the Koeffler lab is studying whether suppressing its working partners may kill Ewing sarcoma cells. Using both computational biology and mathematical modeling, the lab has revealed a number of potential working partners of EWSR1/FLI1, including MEIS1, KLF15, OTX2, etc. For example, the lab has recent shown that MEIS1 co-operates with EWSR1/FLI1 in the promotion of expression of many target genes (Lin, Huang et al. 2018). We are actively studying how these proteins aid the function of EWSR1/FLI1 in the development and progression of Ewing sarcoma. Understanding the molecular roles of these abnormal pathways holds the potential for the identification of innovative and more effective therapeutic treatment of this abnormality.

Sadly, government funding for Ewing sarcoma is poor. Therefore, philanthropic donations are badly needed through the Ewing’s Sarcoma Research Foundation. (H.Koeffler@cshs.org)

Some Useful References

Anderson ME, Randall RL, Springfield DS, Gehhart MC. Sarcomas of bone in Niderhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE eds. Abeloffs Clinical Oncology, 5th ed. Philadelphia, Pa: Elsevier; 2014
DeLaneyTF, Hornicek FJ. Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of tumors. UpToDate 2018
Lin L, Huang M, Shi X, Mayakonda A, Hu K, Jiang YY, Guo X, Chen L, Pang B, Doan N, Said JW, Xie J, Gery S, Cheng X, Lin Z, Li J, Berman BP, Yin D, Lin DC, Koeffler HP. Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1. Nucleic Acids Res. 2018 Nov 28. doi: 10.1093/nar/gky1207. PMID: 30496486
Sun H, Lin DC, Cao Q, Pang B, Gae DD, Lee VK, Lim HJ, Doan N, Said JW, Gery S, Chow M, Mayakonda A, Forscher C, Tyner JW, Koeffler HP. Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma. Clin Cancer Res 2017 Mar 23. doi: 10.1158/1078-0432.CCR-16-2185. PMID: 28336564
Sun H, Lin DC, Cao Q, Guo X, Marijon H, Zhao Z, Gery S, Xu L, Yang H, Pang B, Lee VK, Lim HJ, Doan N, Said JW, Chu P, Mayakonda A, Thomas T, Forscher C, Baloglu E, Shacham S, Rajalingam R, Koeffler HP. CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling. Cancer Res. 2016 May 1;76(9):2687-97. PMID: 26956669
Lin, L., M. Huang, X. Shi, A. Mayakonda, K. Hu, Y. Y. Jiang, X. Guo, L. Chen, B. Pang, N. Doan, J. W. Said, J. Xie, S. Gery, X. Cheng, Z. Lin, J. Li, B. P. Berman, D. Yin, D. C. Lin and H. P. Koeffler (2018). “Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1.” Nucleic Acids Res.