Kelly M. Bailey, MD, PhD, is a sarcoma specialist in the Division of Pediatric Hematology/Oncology at UPMC Children’s Hospital of Pittsburgh who is interested in sarcoma biology and the impact of the EWS-FLI1 fusion oncoprotein on the Ewing sarcoma tumor microenvironment. Dr. Bailey’s research is focused on Ewing sarcoma and its metastatic pathways, and how microenvironmental stresses can affect both primary and metastatic disease states and progression. Determining why certain individuals’ cancers behave more aggressively is of primary importance for Dr. Bailey, given the fact that relapsed and refractory cases are challenging to treat successfully.
Dr. Bailey’s early research efforts were recognized by the Alex’s Lemonade Stand Foundation, when they awarded her one of their 2016 Young Investigator Grants. The three-year, $150,000 award is funding Dr. Bailey’s research project titled ”Micro-environmental Regulators of Ewing’s Sarcoma Metastasis.” In March 2018, Dr. Bailey was awarded an Emerging Scientist Grant from the Children’s Cancer Research Fund® (CCRF) to help further her research into the signaling pathways that cause some Ewing sarcoma cells to become more aggressive and less sensitive to chemotherapy. The $100,000 award from the CCRF is designed to support young investigators to develop independent research. In October of this year, Dr. Bailey was awarded a Hyundai Hope on Wheels® grant that will help further her sarcoma research.
Dr. Bailey also is a part of the recently formed New Agents for Ewing Sarcoma Task Force of the Children’s Oncology Group (COG). Dr. Bailey is one of 10 investigators comprising the task force.
The vast majority (75 to 80 percent) of Ewing sarcoma tumor cells express the EWS-FLI1 fusion oncoprotein (transcription factor). EWS-FLI1 is an abnormal protein not found in normal cells. It is created through a chromo-somal abnormality and linkage between chromosomes 11 and 22, the fusion of which created the abnormal fusion oncoprotein.
Dr. Bailey’s new paper1 in the journal Oncotarget details her team’s work and findings into how the EWS-FLI1 fusion oncoprotein is formed and how it can influence or mediate the way T cells can or cannot recognize the Ewing sarcoma tumor cells and target them for immune response and ultimate destruction. Dr. Bailey’s research specifically looked at the effect of EWS-FLI1 on CD8-positive T cells and the cytokine interferon-gamma.
Ewing sarcoma cells can dynamically express high or low levels of the EWS-FLI1 protein, and there can exist much intratumor cell heterogeneity with respect to EWS-FLI1 protein levels. Recent research in the field has that varying levels of EWS-FLI1 can significantly influence cellular behavior, with those in low states highly prone to metastasize.
Previous work by Dr. Bailey also has shown that Ewing sarcoma cells with low levels of EWS-FLI1 tend to overexpress ICAM-1, a protein that aids in T cell activation and interaction between tumor cells and T cells.
“Our original hypothesis was that since low EWS-FLI1 cells overexpress ICAM-1, T cells would be better able to recognize these cells and target them for destruction. However, our research actually uncovered the opposite effect from what we expected to see. Although these tumor cells do express more ICAM-1, they appeared to be more resistant to the T cell response,” says Dr. Bailey.
The reason for this contradictory response appears to be because the low-state EWS-FLI1 Ewing sarcoma cells upregulate both PD-L1 and PD-L2. With more PD-L1 and 2 available on a tumor cell, it can bind to the PD-1 and 2 receptors on the T cell and reduce or turn off the immune response, thereby evading detection.
Dr. Bailey’s paper, however, goes on to show that when they blocked PD-L1 expression in the tumor cells with low levels of EWS-FLI1, they were able to increase the efficacy of the T cell response compared against tumor cells with higher levels of EWS-FLI1.
Two things about Ewing sarcoma are firmly understood: There exist great levels of heterogeneity within the tumor and within the individual cells of the tumor, and that very little is currently understood about the micro-environment of these tumors and how these factors influence growth, mechanisms of metastasis, and suppression or evasion of the immune response.
“The overarching goal of our research is to better understand these aspects of Ewing sarcoma, how and why there is so much cellular variability in these tumors, and the methods by which we can work on improving therapies that target all of these important pathways that make some cells more responsive to therapy and others less so,” says Dr. Bailey.
The work is challenging for these reasons, and also compounded by the fact that there are no good animal models currently available for Ewing sarcoma, partly because of the heterogeneity that exists, and partly because the field has yet to understand fully the exact cell of origin in these tumors and what other factors or influences on cells at a specific point in development lead to tumorigenesis.
For Dr. Bailey, this paper and its findings are an initial step to understanding how EWS-FLI1 might be regulating tumor cell immunogenicity and the cell’s response to interferon-gamma. While it may be the first step, new research is already underway that will continue to advance Ewing sarcoma cell biology. Dr. Bailey indicates that future work will look more specifically at the role of interferon-gamma and other aspects of the immune response to these tumors.
1 Bailey KM, Julian CM, Klinghoffer AN, Bernard H, Lucas PC, McAllister-Lucas LM. EWS-FLI1 Low Ewing Sarcoma Cells Demonstrate Decreased Susceptibility to T-Cell-Mediated Tumor Cell Apoptosis. Oncotarget. 2019; 10(36): 3385-3399.
Hawkins AG, Julian CM, Konzen S, Treichel S, Lawlor ER, Bailey KM. Microenvironmental Factors Drive Tenascin C and Src Cooperation to Promote Invadopodia Formation in Ewing Sarcoma. Neoplasia. 2019 Sep 12; 21(10): 1063-1072. Epub ahead of print.
Venier RE, Maurer LM, Kessler EM, Ranganathan S, McGough RL, Weiss KR, Malek MM, Meade J, Tersak JM, Bailey KM. A Germline BARD1 Mutation in a Patient With Ewing Sarcoma: Implications for Familial Testing and Counseling. Pediatr Blood Cancer. 2019 Sep; 66(9): e27824. Epub ahead of print.
Bailey K, Cost C, Davis I, Glade-Bender J, Grohar P, Houghton P, Isakoff M, Stewart E, Laack N, Yustein J, Reed D, Janeway K, Gorlick R, Lessnick S, DuBois S, Hingorani P. Emerging Novel Agents for Patients With Advanced Ewing Sarcoma: A Report From the Children’s Oncology Group (COG) New Agents for Ewing Sarcoma Task Force. F1000Res. 2019 Apr 15; 8. pii: F1000 Faculty Rev-493. doi: 10.12688/f1000research.18139.1. eCollection 2019. Review.
Bailey KM. Prospective Investigation of Drug Resistance: An Approach to Understanding and Optimizing the Clinical Benefit of Targeted Agents in Ewing Sarcoma. Oncotarget. 2018 Dec 18; 9(99): 37270-37271.