Ewing sarcoma is a rare and debilitating type of bone cancer affecting young adults and children. Despite intensive treatment with chemotherapy, surgery, and radiation, many children do not overcome the disease.
Pediatric oncologists Ian Davis, MD, PhD, and Justin Sperlazza, MD, PhD, at the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center are working to expand treatment options and advance studies of pediatric solid tumors with the latest immunotherapies, like chimeric antigen receptor T-cell (CAR T-cell) therapy, which trains a patient's immune system to target and eliminate tumor cells.
Ian Davis, MD, PhD
In a new paper published in Molecular Cancer Therapeutics, Drs. Davis and Sperlazza identified drugs that make Ewing sarcoma cells more vulnerable to CAR T-cell therapy. The promising preclinical findings could help guide future clinical trials for children and young adults with sarcomas.
"New therapeutic strategies are really needed for patients with bone cancer that either don't respond to upfront therapy or experience relapse of the disease," said Dr. Sperlazza, who is first author on the paper. "Now that we know that our strategy works, we believe that we are on the cusp of getting this combination therapy to clinical trials."
Bringing their expertise in gene regulation, Davis and Sperlazza partnered with fellow UNC Lineberger Comprehensive Cancer Center member and pediatric oncologist Barbara Savoldo, MD, PhD. Dr. Savoldo has been developing the next generation of CAR-T cells that target GD2, a molecule found on the surface of some cancer cells. GD2 acts as a beacon to help immunotherapies recognize and target tumors.
Barbara Savoldo, MD, PhD
However, researchers needed a way to force GD2 to "turn on" in Ewing sarcoma cells. Sperlazza ran a series of tests with the help of Eshelman School of Pharmacy's Center for Integrative Chemical Biology and Drug Discovery to see what drugs could do the job. They found two drugs with potential: tazemetostat and entinostat.
Drs. Davis and Sperlazza then tested the drugs in a preclinical Ewing sarcoma model. They found that combining tazemetostat and entinostat helped GD2-specific CAR T-cells more effectively target Ewing sarcoma cells. Notably, more than half of the models that received the combination therapy were disease-free by the end of the study.
Following their new findings on CAR-T cell therapy, the Davis lab is focused on seeing if their GD2 strategy is equally effective for other cancer drugs and non-experimental immunotherapies, like antibody therapies. Davis states that using pre-existing therapies will help fast-track their findings to clinical trials and, most importantly, to patients in need.
"For families and kids with Ewing sarcoma, the current treatment is exhausting," said Dr. Davis. "It is marked by frequent hospital admissions and clinic visits, as well as significant side effects. We have the opportunity to help improve the lives of these kids with new therapies that minimize toxicity and can improve overall health outcomes."
This work was supported by the V Foundation (Grants AST2023-003 and T2020-003 to IJD and BS) and the National Cancer Institute (R01CA276663 to IJD).
