Currently, no good therapy exists for Ewing Sarcoma (EWS), a type of bone cancer in children and adolescents that has an aggressive disease phenotype and poor prognosis. EWS occurs most commonly in the second decade of life, with a rate of 0.3 cases per million in children younger than 3 years of age, and as high as 4.6 cases per million in adolescents aged 15–19 years. Long-term survival for metastatic EWS is <20%. A rare pediatric cancer, EWS has received little attention from researchers and less interest from pharmaceuticals to develop new drugs. Our goal is to develop a precision therapy against EWS that is safe and effective with minimal side effects, and which spares normal develop...

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Currently, no good therapy exists for Ewing Sarcoma (EWS), a type of bone cancer in children and adolescents that has an aggressive disease phenotype and poor prognosis. EWS occurs most commonly in the second decade of life, with a rate of 0.3 cases per million in children younger than 3 years of age, and as high as 4.6 cases per million in adolescents aged 15–19 years. Long-term survival for metastatic EWS is <20%. A rare pediatric cancer, EWS has received little attention from researchers and less interest from pharmaceuticals to develop new drugs. Our goal is to develop a precision therapy against EWS that is safe and effective with minimal side effects, and which spares normal developmental tissues in children. Towards that goal, we have identified a novel target called Stag2 (SA2), a protein important for cell division. Recent studies have reported pathogenic mutations in the SA2 gene in approximately 21% of relapsed EWS tumors. The finding of the SA2 mutation is particularly noteworthy because, like most pediatric cancers, EWS harbor very few genetic mutations in the tumor tissue. Our lab has identified a compound, which we named stagX1, that selectively kills SA2-mutant EWS cells, with no or very little effect on normal cells, by inhibiting a related gene called SA1. This process, known as synthetic lethality, occurs when the simultaneous perturbation of two genes results in cellular death. Targeting tumor suppressor genes often mutated in tumors through synthetic lethality is a new paradigm for cancer treatment. Clinically relevant synthetic lethal agents such as stagX1, which kills SA2-mutant cells by synthetic lethality, is targeted and advantageous over the current “kill them all” chemotherapy. Therefore, our proposal to develop a precision drug against SA2 mutations, a novel and untested therapeutic target, to treat EWS is timely and innovative, and will significantly impact the treatment of relapsed EWS tumors.

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