Identification of Drivers of Metastasis-Initiating Cells in Ewing Sarcoma
Abstract
Ewing sarcoma is the second most common bone cancer in children and young adults, and this proposal directly addresses the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area “Pediatric, adolescent, and young adult cancers.” Over the past six decades, the intensification of Ewing sarcoma therapy has gradually improved the cure rate for many patients. Until the introduction of conventional chemotherapy drugs in the 1960s, large, invasive surgeries, often involving amputations, cured less than 10% of patients. For the next 30 years, the gradual introduction of chemotherapy drugs guided by “more is better” has led to the current standard of care, which consists of giving five toxic conventional chemotherapy drugs in high dosing every 2 weeks over 7 months, often combined with surgery and radiation. Despite this extremely toxic therapy, up to 30% of patients with lower-stage disease and 80% of patients with advanced disease still eventually die. Significantly, therapy improvement has essentially stalled for the past 20 years, with multiple failed trials. The pattern of treatment failure is almost exclusively due to the tumor spreading to other organs (called metastasis), mainly to the lungs. Despite these clinical observations, many targeted therapies currently being studied are focused on and evaluated by local tumor response but do not stop the metastasis. This shortcoming fails to address the most pressing need: the prevention and treatment of metastatic disease. To address this need, our laboratory, as well as others, have recently started focusing on how we can specifically target metastasis in Ewing sarcoma. Recently, there have been new discoveries indicating that Ewing sarcoma tumors contain a range of cancer cells that have much more diversity than previously thought, although which cells exactly give rise to metastasis and how to target them remains unknown. Using a unique mouse tumor metastasis model we have developed that closely mimics human disease progression and metastasis, we propose to identify (1) Which cells within the tumors give rise to metastasis, and (2) The specific druggable vulnerabilities of these cells. We expect that the identification and characterization of the specific cells within the tumor that give rise to metastasis will further lead to the identification of multiple potential novel anti-metastasis treatment options. While our proposal is basic in nature, we are specifically focusing on potential druggable targets, and we anticipate the swift translation of these findings to clinical trials within several to 10 years through a 23-institute clinical trial network. The research proposed here directly responds to the military relevance focus area regarding “gaps in cancer prevention, early detection/diagnosis, prognosis, and/or treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public.” Ewing sarcoma affects adolescents and young adults, a population heavily represented in the armed forces, which leads to the disproportionate burden of this disease on mission readiness as well as the direct impact of this disease on the well-being of many Service Members and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110470
Entities
People
- Masanori Hayashi
Organizations
- United States Army
- University of Colorado Denver