Targeting tumor associated macrophages in metastatic Ewing sarcoma (ES)
Ewing sarcoma (ES) is a malignant tumor arising from bone and soft tissue in children, adolescents, and young adults (CAYA). Most ES patients already have tumor cells spread (metastasis) to other organs such as lung and bone at the time of diagnosis. Despite the intensive treatment including surgery, radiation, and chemotherapy, only approximately one out of four patients with metastatic ES will survive 5 years. More effective and new therapeutic approaches are desperately needed to improve survival of these patients.
These new approaches likely will come from a better understanding of why and how ES tumor cells spread. CD47 is a protein highly expressed on many types of tumor and sends out a “don’t eat me” signal to the immune cells, mostly macrophages (the white blood cell that kills bacteria in infection sites), so that tumor cells can escape macrophage killing and spread to other organs. Additionally, tumor cells turn down the expression of “eat me” signals, a protein called calreticulin (CRT), as another way to escape macrophage killing.
Recent findings from our group and others show that CD47 expression level on ES cells is high and associated with poor patient outcome, whereas CRT is not expressed on most cases of ES. In this proposal, we will test whether blocking CD47 and at the same time inducing CRT expression work together to effectively boost macrophage killing and inhibit ES tumor progression/spreading, and therefore serve as a new effective approach to improving the outcome of CAYA patients with metastatic ES.
Project Goals:
Therapy improvement in Ewing sarcoma (ES) has essentially stalled for the past 30 years, in large part due to the treatment failure to prevent the tumor spreading to other organs, called metastasis. Children with metastatic disease have dismal survival (<25%) and desperately need new effective therapies. One of our immediate project goals is to evaluate the effectiveness of new approaches to preventing ES growth and spreading by maximizing immune cell (macrophage) killing of ES cells.
Another immediate goal of our project is to better understand what genes and proteins in ES cells are important in macrophage-associated ES spreading and how the other immune cells in the patients’ immune system play a role in this process. We believe that we have the appropriate and unique tools and techniques to reach these goals. The treatment regimens we will test in this proposal are either currently used in the clinic treating ES patients or under clinical/preclinical testing in patients/animals with other diseases and have shown to be safe, tolerable and effective.
The successful completion of our short-term goals will help us reach our long-term goal, which is to rapidly move these novel therapeutic approaches into a clinical testing and improve the outcome of children, adolescents, and young adults with advanced (metastatic) ES, who are in desperate need of new effective therapy.
Project Update 2024:
In this ALSF Innovation grant, we proposed to test whether blocking CD47 and at the same time inducing CRT expression work together to effectively boost macrophage killing and inhibit ES tumor progression/spreading, and therefore serve as a new effective approach to improving the outcome of CAYA patients with metastatic ES. In the past two years, we successfully reached our project goal which was to evaluate the effectiveness of the above new approach to preventing ES growth and spreading by maximizing immune cell (macrophage) killing of ES cells. We also performed mechanistic studies which led to better understanding of what genes and proteins in ES cells as well as macrophages are important in macrophage killing of ES cells. Our data provided evidence that the new approach we proposed is effective in significantly increasing macrophage killing of ES cells and decreasing ES tumor growth and spreading in preclinical studies. The treatment regimens we tested in this project are either currently used in clinic treating ES patients or under clinical testing in patients with other diseases and have shown to be safe, tolerable and effective. We hope that this novel effective therapeutic approach will soon be translated into a clinical testing and improve the outcome of CAYA with advanced (metastatic) ES, who are in desperate need of new effective therapy.
