Identification and characterization of non-P53 stress pathways in Shwachman-Diamond syndrome
Mentor Name: Seth Corey
At least 10% of children with cancer have inherited a mutated gene that predisposed them to develop a cancer. With gene sequencing being applied more frequently to children with or without syndromes, parents will be anxious about that date. Doctors will want to identify risk factors and develop prevention strategies to reduce those cancer risks. One critical step toward preventing cancer would be to identify the "stress" pathways caused by the mutated genes and develop safe drugs or behaviors. We are studying one of those cancer predisposing genes, SBDS, which when mutated causes Shwachman-Diamond syndrome (SDS). Typically, these children are smaller than their peers, do not absorb proteins and fats because of pancreatic insufficiency, and develop a deficiency of white blood cells (and sometimes red cells and platelets). In individuals with SDS, there is a 1000-fold increased risk of developing myeloid leukemia. They also are prone to non-blood cancers involving the pancreas or breast. The Corey lab has developed unique experimental systems in fish and cell lines. Their leukemias are often resistant to chemotherapy, and they have increased side effects to a bone marrow transplant. It is therefore best to prevent cancer formation with safe medicines, just like taking an aspiring to prevent a heart attack or stroke. I will assess one pathway, the stress-activated protein kinase, and evaluate the ability of a drug to inhibit this pathway. I hope that my work will lead to better prevention of cancer formation in this pediatric disease and would serve as an example for other cancer predisposition syndromes.