Childhood Cancer

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Exploiting the Potential of Bromodomain Inhibitors in Ewing Sarcoma

Seattle Children’s Hospital
Shireen Ganapathi, MD
Grant Type: 
Young Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Ewing Sarcoma
Project Description: 

Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor affecting adolescents and young adults (AYA), and compromises about 250 pediatric and AYA cancer diagnoses yearly. With intensive therapy, survival has improved for patients with a single tumor at diagnosis, but this treatment strategy has not been effective in patients with disease present in multiple areas at diagnosis, and very few successful treatment options exist for disease that recurs following completion of initial therapy. To improve survival for these high risk ES patients, we need to streamline testing of therapeutic agents and understand further how the biology of ES leads to tumor growth and spread. Bromodomain and extraterminal domain protein (BET) inhibitors are a class of drugs that alters a specific tumors ability to turn on genes that are critical for its survival and propagation. Many tumors, including ES show striking results with BET inhibitors in the lab, but like many agents are not curative alone. Thus my proposal will identify efficacious drug combination strategies with the BET inhibitor, BMS-986158, with future goal of translating the most successful combinations to high risk patients, and identify how ES can escape BET inhibition to identify additional targets for treatment.

Project Goal
The goals of my proposed project are to improve therapies for adolescents and young adults with Ewing sarcoma who present with multiple tumors at diagnosis (metastatic) or have recurrence of their disease following initial treatment. Because we know that for these patients treatment options are limited, and also that intensifying treatment for patients with metastatic disease has not proven to be effective, my project goals will focus on combining newer targeted therapies that work by affecting certain aspects of Ewing sarcoma tumors. The goal will be to identify different targeted drugs that can be safely used in combination and effectively treat high risk Ewing sarcoma patients. Additionally, we are still learning about Ewing sarcoma and trying to answer questions such as why certain tumors present in multiple sites, or why certain tumors are resistant to the treatments that we give. The other goal of my project will be to identify ways that Ewing sarcoma tumors have figured out how to escape the therapies we treat them with, and use this information to improve the delivery of these newer targeted therapies so they can be used effectively in patients. Ultimately with the information gained from this project, my hope is that we will improve treatment and outcomes for our most vulnerable Ewing sarcoma patients.