Developing Novel Treatment for Ewing Sarcoma: Q&A With Patrick Grohar, MD, PhD

Dr. Patrick Grohar, MD, PhD, a world leader in Ewing sarcoma research who joined the ranks of Children’s Hospital of Philadelphia in 2019, is developing a novel treatment — with the aim of opening a clinical trial soon — for children with this disease who relapse after receiving traditional treatment. Ewing sarcoma is a rare form of bone cancer that affects children, adolescents, and young adults and is characterized by chromosome changes that occur after birth.

We caught up with the physician scientist to discuss his new role as director for Translational Research with the Center for Childhood Cancer Research and the innovative treatment for Ewing sarcoma involving two approved chemotherapies that, when combined, lab research has suggested can inhibit a key mutation involved in the disease. Dr. Grohar is also on faculty in the Perelman School of Medicine at the University of Pennsylvania.

Q: Why are you excited to be at Children’s Hospital of Philadelphia as the director for Translational Research with the Center for Childhood Cancer Research?

A: It’s a unique opportunity. CHOP is a fantastic place and phenomenal at pediatric hematology-oncology — from neuroblastoma to leukemia, transplant, and hematology. I came here because there was a need to grow the sarcoma program. I’m excited to help contribute to building that program and to try to help patients with sarcoma, mainly through translational work.

Q: How does your role as an attending physician for the Cancer Center at CHOP help you to be successful as the director of Translational Research and vice versa?

A: There’s a wealth of expertise on the campus in science, translational science in particular, and a wealth of clinical expertise and knowledge, so to be in both camps is an outstanding opportunity. It’s great to work alongside some of the best sarcoma clinicians in pediatrics anywhere — Naomi Balamuth, MD; Rick Womer, MD; Rochelle Bagatell, MD — and at the same time, be in such an upstanding, wonderfully rich environment for science.

My goal for the next 10 years is to try to get the bench and bedside as close as they can be and to leverage technology that’s used routinely in the lab to help patients in the clinic. CHOP is the place where you can make that happen — where you can try to bring these technologies to the patients and take what you learn from the patients back to the lab.

Q: Tell us about some current or upcoming translational research projects the Center for Childhood Cancer is pursuing that you’re enthusiastic about?

A: A number of exciting studies span every field in pediatric oncology from late effects to other solid tumors, leukemia, brain tumor to immunotherapy to tumor predisposition, that are truly leading the way in the field. It makes it an exciting place to work. I think I am most impressed with where the neuroblastoma field is here at CHOP. Drs. John Maris, and Yael Mosse, have a couple of studies that leverage what has been done and what they are currently doing in the lab to bring this to patients through, for example, the ALK inhibitor and NEPENTHE (Next Generation Personalized Neuroblastoma Therapy) studies. In addition, Dr. Bagatell is leading the way nationally through a molecular and risk-stratified study in the Children’s Oncology Group that is very impressive. These types of studies need to happen in sarcoma.

Q: What motivated you to study sarcomas, and particularly Ewing sarcoma, in the pediatric population?

A: It was a patient. We all have patients who reach us when we train. As a fellow, you do your first year in the clinic and the next two years in the lab. The first patient I saw as a fellow was a 17-year-old who had Ewing sarcoma. He was diagnosed on my first day, actually. We treated him, and his tumor eventually went totally away. But then, on my last day as a first-year clinical fellow — he died. Certain patients reach you; they all reach you on some level, but this young man ... I felt I had to do something about that.

Q: Can you explain the importance of chromosomal translocation in sarcomas and how your research is exploring this process to find new drug targets?

A: Many sarcomas are driven by a particular mutation called a chromosomal translocation that generates a transcription factor. In the translocation positive sarcomas that we study, like Ewing sarcoma, it is quite clear that the fusion proteins that result from the chromosomal translocations are the oncogenic driver responsible for the cancer.

The challenges are that the balanced chromosomal translocations produce oncogenic transcription factors that alter the expression of more than 500 genes to drive tumorigenesis and progression. These transcription factors are felt to be undruggable targets because of their physical shape; there’s no obvious place to put a molecule to block function. We are working hard on trying to find ways to drug these targets because the tumor completely depends on them. It’s pretty widely accepted that if we could figure out ways to drug these particular targets, the likelihood of having them be successful in the clinic is high.

Q: Your research with the two chemotherapies, trabectedin and irinotecan, is making great progress. Can you bring us up to date on your work and its implications for the future of sarcoma research?

A: One of our studies, “SARC037: A Phase I Study to Evaluate the Safety of Trabectedin in Combination With Irinotecan in Ewing Sarcoma Patients,” that we’ve worked on for many years in the laboratory, is translating to patients probably in the next month. It’s been known for about 20 years that this tumor, Ewing sarcoma, is dependent on the continued activity of a particular target called EWS-FLI1, the defining molecular lesion of Ewing sarcoma.

My lab has spent the last decade trying to figure out ways to identify vulnerabilities in this particular drug target. We’re repurposing a drug that’s been active in a lot of tumors as a targeted agent for this disease. We’ve spent years working out how it works, how to effectively administer it to make it inhibit EWS FLI1, and to develop biomarkers so that we can give the drug to patients, do a PET scan, and see whether or not we’ve hit the target. This clinical study opens in the next month, and I’m really excited about it.

And we have a number of projects in the lab that are extending our findings to other tumor types that I’m super excited about too. A lot of really cool stuff is going on right now.

Q: What do you enjoy most about the translational nature, the bench to bedside and back again aspect, of your research on the development of new therapies?

A: It’s the opportunity to impact patients — there’s no question about it. The idea that we can do something in the lab and then within a year or two see it in patients is quite exciting. You hear about these patients all the time throughout the country. They have relapsed disease, and they’re not doing well. You go into this field and choose to focus on the lab to try to help these patients, and with this type of research, you can make an impact.

There’s another side to it too. I recruit young people, graduate students, post-baccalaureate students, and clinical fellows to work on these projects. You can tell them, “If you come to my lab, you can work on this, and it could, and likely will, reach patients.” Channeling the enthusiasm of young people into this problem and helping them help others — that’s incredible.