Profile of a Cancer: Getting to Know Ewing Sarcoma

The father of the field of oncology, James Ewing, MD – the man behind the American Cancer Society and the Journal for Cancer Research – first described his eponymous cancer cells in a published case series in 1921.

The modern characterization of Ewing sarcoma still agrees with Dr. Ewing’s initial description: It affects both flat and long bones, most commonly appearing in the legs and arms, pelvis, trunk, or head and neck. It primarily affects adolescents and requires radiation therapy. Current treatment modalities add in aggressive surgery, chemotherapy and combination therapies, especially in the case of metastatic or recurrent disease.

Ewing sarcoma affects about 10 out of every 1 million people aged 10-19 years. When combined with similar cancer subtypes, Ewing and related sarcomas become the fourth most common cancer among children and young adults.

Unfortunately, Ewing sarcoma is notoriously difficult to treat. Prognosis depends on age at diagnosis, the location of the tumor, metastasis, sex, certain genetic differences in Ewing sarcoma subtypes, and the patient’s cancer-related history, among other traits. Despite many advances in therapy and survival in the past several decades, researchers and clinicians alike have become frustrated with the uphill battle facing Ewing patients.

“We can palliate or comfort patients with metastatic Ewing sarcoma, and hold off the inevitable for a few years, but that’s not enough. Our goal is a cure,” says Timothy Cripe, MD, PhD, chief of the Division of Hematology/Oncology/Blood and Marrow Transplant at Nationwide Children’s Hospital and a clinician-scientist studying Ewing and other pediatric cancers. “It’s incredibly frustrating as a doctor to see patients week after week and know that they’re in trouble.”

Dr. Cripe and his research team have been studying ideal combination therapies for Ewing tumors. Recent publications reveal a promising synergy between two FDA-approved therapies: an oncolytic herpes virotherapy and trabectedin, a chemotherapy drug with a less toxic side effect profile than many currently in use. When given together to a mouse model of Ewing sarcoma, trabectedin appeared to clear out about half of the tumor’s macrophages, which fight infection and spur wound healing. Once macrophage levels dropped, the virotherapy effectively raised inflammation in the tumor, helping the immune system better fight the tumor.

Manipulation of the tumor microenvironment to attack cancer cells is also under study by other investigators. Elizabeth Lawlor, MD, PhD, associate director of education and training at the Rogel Cancer Center and an associate professor in the departments of Pediatrics and Pathology at the University of Michigan, is one of the researchers behind recent studies indicating that the origin of Ewing sarcoma appears to be hijacked stem cells that were originally destined to become bones and supporting soft tissues. Her lab is also analyzing the factors in the tumor’s surrounding cells that trigger the switch from progressive growth as a solitary tumor to migration and metastasis.

“My lab is trying to figure out how cells switch back and forth between different states, and which pathways drive these switches, since we are finding that the ability of Ewing cells to change states is essential for tumor progression,” says Dr. Lawlor. “We want to know how cells come to play different roles at different times. Then if we can find a way to interfere with those transitions, that could be a good way to inhibit tumor survival and prevent metastasis.”

To speed along the identification of druggable targets, some teams are focusing on screening Ewing sarcoma for its genomic vulnerabilities. Patrick Grohar, MD, PhD, associate professor and program leader of Skeletal Disease and Cancer Therapeutics in the Van Andel Research Institute’s Center for Cancer and Cell Biology – a chemist by training, prior to his foray into medicine and oncology – cast a wide net in his initial search for potential drug options.

Dr. Grohar set about doing a genome-wide small molecule screen for 50,000 compounds, looking at what kills or turns off the fusion protein, and has screened with other large libraries of compounds as well. His work first revealed that mithramycin inhibits the fusion protein. The screens also demonstrated the EWS-FLI-inhibition abilities of trabectedin – the chemotherapy drug now used by Dr. Cripe in his preclinical studies.

“Ewing sarcoma is driven by a transcription factor. The mantra when I was in med school was that it’s a non-druggable target,” says Dr. Grohar, who is also an oncologist in the Division of Pediatric Hematology/Oncology at Spectrum Health Helen DeVos Children’s Hospital and an associate professor in the Department of Pediatrics at Michigan State University. “But as a chemist I believe everything is druggable. You just have to figure out how to do it.”

After identifying compounds with anti-Ewing potency, Dr. Grohar does in-depth molecular and preclinical testing to determine which may be good drug candidates. Mithramycin is currently in clinical trials, and Dr. Grohar hopes that continued research will reveal more effective second- and third-generation iterations of screen-identified compounds that he can also quickly transition to the clinic.

Taking a similar approach, Kimberly Stegmaier, MD, vice chair of pediatric oncology research and co-director of the Pediatric Hematologic Malignancy Program at the Dana-Farber Cancer Institute, used genome-scale CRISPR-Cas9 screening (a gene editing tool) to find druggable target pathways in TP53 wild-type Ewing sarcoma – a form that differs from many cell line models of the disease but that represents the cancer more accurately as it occurs in most human patients.

Her search revealed multiple possible targets (MDM2, MDM4, USP7 and PPM1D) critically involved in cancer survival, some of which already had compounds available to test for in vitro impact on human Ewing cell lines and mouse models. After successful and synergistic lab-based studies, this p53 pathway activation approach has entered clinical trials in children with Ewing sarcoma and other childhood cancers with a normal TP53 gene. Dr. Stegmaier also has NCI Cancer Moonshot U54 funding to find new therapies for Ewing sarcoma.

To make an even broader view of Ewing sarcoma’s genomic make-up possible, Dr. Lessnick collaborates with teams led by Richard Wilson, PhD, and Elaine Mardis, PhD, co-executive directors of the Institute for Genomic Medicine at Nationwide Children’s, to do a long-read genomic sequence of Ewing sarcoma. One cell line is complete, and Dr. Lessnick has several others in progress or planned.

Ideally, long-read sequencing will reveal the true locations of certain genes and hint at the purpose and weaknesses of various chunks of the cancer’s DNA.

“Ewing sarcoma serves as a paradigm for a whole series of tumors seen in children, adolescents and young adults,” says Dr. Lessnick. “Better understanding Ewing sarcoma could have direct impact on our ability to treat rhabdomyosarcoma, clear cell sarcoma, desmoplastic small round cell cancers, and a variety of tumors with translocations that generate transcription factors.”

Dr. Stegmaier agrees that discoveries in Ewing sarcoma could mean big advances in other diseases.

“The approaches and technologies that are used to study EWS/FLI could be applied to studying the host of other fusion proteins present in pediatric and adult cancers, such as the TMPRSS2/ERG fusion in the majority of adult prostate cancer tumors,” says Dr. Stegmaier, who is also an attending oncologist at Boston Children’s Hospital.

Recent dramatic successes in chemically targeting kinase fusions, which relate to but are more readily druggable than transcription factors, provide incentive for persevering toward targeting fusions such as EWS/FLI. Moreover, new advances in chemistry offer hope for success in targeting EWS/FLI directly – hence Dr. Stegmaier’s U54 proposal to collaborate heavily with academic chemists in her upcoming research. Once these molecular components are targetable, cancers with similar structural proteins, fusions and transcription factors may also benefit.

The disease also offers researchers a uniquely distraction-free “background” for studying cancer.

“Because Ewing sarcoma in particular, and pediatric cancer in general, are genetically very quiet tumors, not full of thousands of mutations, we can do cleaner genetic and biology studies. These studies are much more challenging with cancers that have scrambled genomes, like you find in most adult carcinomas,” says Dr. Lawlor. This fact also gives Dr. Lawlor hope that Ewing may, when the right biology is understood, become highly treatable.

“The concept is that pediatric cancers can be considered developmental disorders, created when plastic stem cells are hijacked to become a sort of cancer stem cell,” says Dr. Lawlor. “You don’t need 50 mutations to create a cancer stem cell, you just need a couple to give a normal stem cell malignant properties. It didn’t take as much to create them, and so hopefully it will not take as much to dismantle them.”

Drs. Lessnick, Stegmaier, and Grohar have Ewing-related clinical studies underway, and Dr. Cripe’s and Dr. Lawlor’s research is expected to hit the clinic in the next few years.

Experts in Ewing sarcoma research agree that treatment advances will, at least in the near future, involve sophisticated regimens of therapy administration and carefully timed and dosed combinations of epigenetic and chemotherapy drugs. They are also working to combat the toxicity of current therapies, as many surviving Ewing patients suffer from long-term treatment-related side effects.

“We have a great field in Ewing sarcoma because we all are willing to talk to each other – we share our unpublished data and what we’re thinking,” says Dr. Lessnick. “Our collaborative, open approach will make a big difference in how quickly we make a difference for patients.”