CCBIO seminar: Caroline Heckman
In vitro drug screens in acute myeloid leukemia
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland
Acute myeloid leukemia (AML) is the second most prevalent leukemia in adults, yet the standard of care treatment consisting of the nucleoside analog cytarabine combined with an anthracycline has remained relatively unchanged for the past 30 years. Better understanding of the pathogenic mechanisms leading to AML have stimulated the development of novel targeted agents, however, inter- and intra-disease heterogeneity pose difficult challenges in finding therapies effective for all patients. Furthermore, while newer drugs exhibit better specificity by targeting signaling pathways that the malignant cells are addicted to, other cell types are often dependent on the same signaling pathways and are similarly affected by the drugs, resulting in off-target effects. Using a systems medicine approach combining high-throughput ex vivo drug sensitivity testing with in-depth molecular profiling by RNA and exome sequencing of cells from AML patients, we can obtain a functional readout of signaling dependencies of the leukemic blasts and at the same time identify molecular indicators for response. Clinical translation of the results has been promising with extended survival of many patients, however, improved methods to assess the efficacy of the drugs in vitro and ex vivo are still needed. Standard high-throughput screening methods primarily provide a readout of cell viability and do not account for the impact of the tumor microenvironment on drug response, or the effect of the drugs on other cell types. To improve ex vivo screening of AML and prediction of response, we have conducted comprehensive assessment of AML drug sensitivity under standard conditions vs. conditions better reflecting the bone marrow microenvironment and identified drug classes impacted by the different conditions. In addition, we have developed a high-throughput flow cytometry platform that allows us to detect the different cell populations that comprise AML patient samples and determine for example the impact of drugs on leukemic vs. healthy hematopoietic stem cells, as well as the impact on other normal cell types. Results from these studies provide information allowing us to develop better drug combinations that can overcome escape mechanisms mediated by the tumor microenvironment, and drugs and drug combinations that can effectively target leukemic blasts while leaving healthy cells intact.
Chairperson: Bjørn Tore Gjertsen, CCBIO