AbstractsBiology & Animal Science

Unraveling prednisolone resistance in pediatric acute lymphoblastic leukemia: towards personalized targeted therapy

by I.M.A.A. Ariës (Ingrid)

Institution: Erasmus University
Year: 2014
Keywords: pediatric acute leukemia; drug resistance; prednisolone; personalized targeted therapy; MCL1; glycolysis; EMP1; NR4A; RAS
Record ID: 1242252
Full text PDF: http://hdl.handle.net/1765/50646


abstract__Abstract__ Optimization of treatment protocols and improved risk stratification have enhanced event-free survival rates in pediatric precursor-B acute lymphoblastic leukemia (BCP-ALL) and T-ALL up to 80-90%. Remarkably, these results are obtained without changing the core chemotherapeutic drugs that have been used for decades, including prednisolone, L-asparaginase and vincristine. To cure the remaining 20% of patients and to reduce long-term side effects in survivors, more personalized targeted therapy is warranted. Novel targeted drugs will most likely serve as adjuvants to current chemotherapy regimens. Prednisolone has been shown to be the most pivotal in treating pediatric BCP-ALL, as in vivo and in vitro response to prednisolone is an important predictor for long-term clinical outcome. Hence, to improve clinical outcome drugs need to be found which reverse resistance to prednisolone. My thesis therefore focused on the identification of genes or mechanisms involved in prednisolone resistance, followed by functional studies to determine the prednisolone sensitizing effects and pathobiology of these genes or mechanisms and subsequently studying target specificity and effectiveness of potential new targeted agents. We have identified several prednisolone resistance mechanisms and have shown that several clinically available inhibitors can target these mechanisms leading to increased prednisolone sensitivity in vitro. These inhibitors could be potential therapeutic treatment options to increase survival in BCP-ALL. For one targeted inhibitor specifically that showed terrific results, we are performing a larger follow-up study to hopefully pave the way for clinical trials.markdown