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Combining targeted therapy and chemotherapy in acute lymphoblastic leukemia
Book - Dissertation
Acute lymphoblastic leukemia (ALL) is a hematological disease, which arises from the malignant T or B cell transformation of developing progenitor cells. It is the most common childhood cancer. Despite the increased overall survival and improved risk stratification, relapse and failure to achieve clinical remission remain major challenges. Further intensification of current treatment regimens is not an option due to the already high toxicity, which leads to severe side effects.To improve the patient's outcome, targeted therapies are being developed which specifically target driver events within the cancer cells. However, the current optimized chemotherapy regimens remain the golden standard, as they are very effective for a large proportion of the patients. Therefore, we have studied how to combine two different types of targeted therapy with the currently used chemotherapy.The first targeted therapy I tested in a combination setting was the JAK1/2 inhibitor ruxolitinib, which can be used for patients that have mutations in the IL7R-JAK pathway. Ruxolitinib proved to be synergistic with the glucocorticoid dexamethasone in T-ALL samples. Next, I tested the exportin 1 inhibitor KPT-8602 in combination with various chemotherapeutics. KPT-8602 is effective against both B- and T-ALL, independent of their mutational status. Again, dexamethasone proved to be the best compound for a synergistic interaction with the targeted therapy. We chose to work with targeted therapies that are already approved or far advanced in clinical trials for other diseases, as this enhances the success rate and the time needed to pass clinical trials.Experimentally, I first defined the most synergistic combinations in vitro, after which I tested the best combinations in vivo in patient derived xenograft (PDX) models. These PDX models allow us to mimic the patient's environment as closely as possible. Finally, I looked closer into the complex mechanism of synergy between KPT-8602 and dexamethasone via different techniques. I found that addition of KPT-8602 enhances the dexamethasone induced glucocorticoid receptor transcriptional activity, leading to a higher induction of target gene expression than dexamethasone alone. Additionally, I showed that dexamethasone treatment leads to the downregulation of E2F target genes, which is also further enhanced by KPT-8602. Altogether, I demonstrate that addition of ruxolitinib or KPT-8602 to dexamethasone is a valuable strategy to enhance the dexamethasone response, which is beneficial for the patients' outcome.