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Ewing sarcoma, an aggressive bone cancer that occurs in children and young adults, is caused by an abnormal chimeric protein (EWS-FLI1) that prevents cells from maturing into normal connective tissues through a process known as cell differentiation. How EWS-FLI1 acts to stop differentiation, however, remains an enigma. To solve this problem, Dr. Ludwig uses powerful gene editing tools to systematically turn the EWS-FLI1 protein up or down, then measures whether such changes allow cancer cells to behave more normally. The information gained from this research is expected to lead to new anti-cancer treatments for adolescents and young adults battling Ewing sarcoma.

This grant is named for The Shohet Family Fund for Ewing Sarcoma Research. Noah was diagnosed with Ewing sarcoma in his freshman year in college. After limb salvage surgery and chemotherapy, he was able to return to school. Two years later, Noah relapsed and sadly passed away. This Hero Fund honors his courageous fight and hopes to raise funds for Ewing sarcoma research.

The shape and function of bone, fat, muscle, and other connective tissues evolve through a carefully orchestrated process that leads mesenchymal stem cells (MSCs) to progressively differentiate into more lineage-restricted tissue-specific phenotypes. As this occurs, MSCs must interpret their surrounding extracellular milieu. When everything works correctly, normal mesenchymal tissues emerge. When disrupted, as tragically occurs with Ewing sarcoma (ES), the aberrant fusion protein (FP) acts as powerful transcription-factor that corrupts the epigenetic program and locks ES in an undifferentiated state unable to interpret or respond to the biophysical cues present in the tumor microenvironment. Attempts to understand the FP’s effect upon tumor-ECM interactions within monolayer culture systems that lack a native tumor microenvironment has contributed, not unexpectedly, to spurious results that overestimate the clinical effectiveness of chemotherapy. To close this gap, Dr. Ludwig's multi-disciplinary team is using an innovative 3D tissue engineered model, pioneered by his laboratory, to assess next-generation EWS-FLI1-targeted therapies within a physiological microenvironment that cannot readily be studied in vivo. This project will shed new light on ES biology and promises to improve the ability to co-target the FP and other proteins that maintain the aggressive, poorly differentiated state of ES.

This grant is generously supported by the Shohet Family Fund for Ewing Sarcoma Research. Noah was diagnosed with Ewing sarcoma in his freshman year in college. After limb salvage surgery and chemotherapy, he was able to return to school. Two years later, Noah relapsed. This Hero Fund honors his courageous fight and hopes to raise funds for Ewing sarcoma research.