Direct targeting of oncoprotein assembly using mimetic peptide interference
Ewing sarcoma occurs in the bone and soft tissue and represents a substantial fraction of cancers affecting children and adolescents. Ewing sarcoma patient’s outcome has substantially improved with the introduction of chemotherapy, and with the current combination of cytotoxic therapy, radiotherapy, and surgical resection, the 5-year survival approaches 70% for some patients. Unfortunately, intensive treatment increases the risk of long-term health problems, including the development of therapy-associated secondary tumors. Importantly, the prognosis for patients with metastatic and recurrent diseases remains dismal, highlighting the need for improved therapeutic options with increased efficacy and reduced toxicity. Ewing sarcoma is caused by an aberrant fusion protein, EWSR-FLI1, exclusively produced by cancer cells. Although several studies have investigated its function, it is still unclear how EWSR-FLI1 activity leads to uncontrolled cell division and tumor formation. The lack of a clear mechanism of action has prevented the development of therapies designed to directly target EWSR-FLI1, limiting progress in the treatment of Ewing sarcoma patients. Investing in new approaches to elucidate the mechanisms controlling EWSR1-FLI1 oncogenicity is a necessary step toward developing safe and effective therapeutics for the Ewing sarcoma patients that do not benefit from available treatments.
Project Goal:
Our goal is to apply a new experimental system, which we developed and tested in preliminary studies, to investigate the role EWSR-FLI1 by using small proteins specifically designed to directly interfere with its activity. Scaffolded interfering peptides (ScIPs) are a reliable tool to investigate EWSR-FLI1 function and a foundation for the future development of Ewing sarcoma targeted therapeutics. In fact, our pilot ScIP can reduce EWSR-FLI1 activity and slow Ewing sarcoma cell growth, but in-depth studies are necessary to elucidate the precise molecular mechanisms behind these observations. This system offers a powerful investigational tool and, at the same time, sets the groundwork for improved design and screening of the next generation of ScIPs. Our goal is to identify essential mediators of EWSR-FLI1 oncogenic activity and to
provide proof of concept of the validity of this approach in preclinical studies, which will guide future research to test the therapeutic applicability of EWSR-FLI1 peptide interference. As fusion oncoproteins, similar to EWSR-FLI1, are prevalent among pediatric and young adult cancers, we anticipate that the development of a generalizable peptide interference screening and design technology would constitute a transformative advance in the understanding and therapeutic targeting of conventionally ‘undruggable’ oncogenic drivers.
