Treatment-Induced Metastasis in Ewing Sarcoma
Abstract
Topic Area: Ewing sarcoma is the second most common bone tumor in children, adolescents, and young adults, and our proposal aims to prevent metastatic spread. This project therefore falls under three PRCRP Topic Areas: pediatric, adolescent, and young adult cancers; sarcoma; and metastatic cancers. Objective and Rationale: Ewing sarcoma is the second most common bone tumor in children, adolescents, and young adults. Patients who are diagnosed with a tumor that has not spread are usually cured. Those who are diagnosed with metastases (the tumor has spread from its initial location) are rarely cured despite decades of clinical trials and intensifying treatment regimens aimed at improving their survival. Our objective is to better understand how Ewing sarcoma cells spread from the initial tumor and then to develop new treatment strategies to prevent this from happening. Our work focuses on a group of cells termed TMEM doorways, which we believe allow sarcoma cells to enter the bloodstream and spread to distant sites. We have made the surprising discovery that after exposure to chemotherapy, tumors have more TMEM doorways, suggesting that chemotherapy could increase tumor cell spread. We have also found that different ways of delivering radiation treatment can affect how quickly mice with Ewing sarcoma die from metastases. We will first directly test whether exposure to either chemotherapy or low doses of radiation directly cause an increase in the number of TMEM doorways and a corresponding increase in disseminated tumor cells, and then we will determine whether drugs that are either already in clinical use or are in development can reverse this effect. What Types of Patients Will Be Helped and How? If our research is successful, our results will change the way patients with Ewing sarcoma are treated. Currently, the first step in treatment is the administration of chemotherapy, and radiation therapy, when used, is given in multiple low doses over 6 weeks. If these ways of treating Ewing sarcoma are found to increase the ability of tumor cells to spread, changing the treatment paradigm would be expected to reduce the risk of metastatic relapse. If there are drugs that can prevent the chemotherapy-mediated increase in TMEM doorways, then adding these drugs to the chemotherapy regimen might be beneficial. If not, patients may benefit from having surgery before chemotherapy is given. If a different way of giving radiation is associated with less tumor cell spread, then the way radiation is administered would certainly change. And if these changes reduce the risk of metastatic relapse, cure rates will improve and fewer patients will die from Ewing sarcoma. Overarching Challenge Being Addressed and Impact: Our work addresses the overarching challenge of Therapeutics because our work seeks to transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis. It will make an impact by altering the way Ewing sarcoma is treated, as described above, in ways that would be expected to decrease metastasis and improve cure rates. Military Health Focus Area: This project addresses the Military Health Focus Area of Gaps in cancer research that may affect mission readiness. Ewing sarcoma is a disease of young adults, who comprise the bulk of military Service Members. It also can affect younger children, who may be the children of Service Members. Ewing sarcoma, therefore, represents a threat to mission readiness by predominantly affecting young adults and their children. Thus, improved treatment, especially prevention of metastasis, will increase military mission readiness by decreasing the chance of an active-duty Service Member being called home due to a relapse of a child’s cancer and by decreasing the risk that an active-duty Service Member will be sent home due to a relapse of their cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310421
Entities
People
- David Loeb
Organizations
- Albert Einstein College of Medicine
- United States Army