CCBIO seminar: Bjørn Tore Gjertsen
Oncogene-addicted cancer: chronic myelogen leukemia as a model of a tyrosine kinase driven malignancy
Bjørn Tore Gjertsen
Centre for Cancer Biomarkers (CCBIO) and Translational Hemato-Oncology Group, Department of Clinical Science, University of Bergen, and Clinical Trials Unit, R&D Department, Helse Bergen
Chronic myelogen leukemia (CML) was the first malignancy connected to a specific genetic change, the 9;22 chromosomal translocation with its BCR-ABL fusion gene. Its natural course without therapy is dramatic and fatal with median survival below five years, usually debuting in a chronic phase, developing into an accelerated phase to finally proceed to a blast phase similar to acute leukemia. The introduction of inhibitor therapy of ABL tyrosine kinase in 2000 dramatically changed this course, and removed the need for stem cell transplant therapy in the vast majority of patients. Five years survival in CML patients on per oral kinase inhibitor therapy is currently above 90%.
Current research in CML is focusing on eradication of the disease and the role of leukemic stem cells (LSC) to understand response to therapy. In the Nordic CML Consortia we have determined LSC number and therapy response in our patients. Immune responses have been correlated with successful CML eradication, and current trials combining kinase inhibitor with interferon-alpha is promising for enhanced LSC eradication. Multiple resistance mechanisms for kinase inhibitors have included mutations in BCR-ABL and cellular transport mechanisms for the kinase inhibitor. Therapy escape mechanisms through specific signaling pathways, like C-KIT and AXL receptor tyrosine kinases, have emerged and the therapeutic tools to test these concepts in future clinical trials are available.
We have used single cell signaling analysis combined with multiparameter flow cytometry and mass cytometry to be able to follow therapy responses in LSC and malignant myelocyte subsets. Single cell analysis of myelocytes from patients treated with kinase inhibitor nilotinib revealed that compared to baseline, phosphorylation of almost all investigated proteins decreases over time, including significant reduction of phospho-Gab2(Y452), p-Abl(Y245), p-STAT5(Y694), p-Erk1/2(T202/Y204), p-p38(T108/Y182) at day 28. Correlation of plasma levels with changes in phosphorylation status revealed a negative correlation of increasing drug levels with decreasing phospho-p38 and phospho-STAT5 status. Single cell analysis allows analysis of both malignant and healthy cells, and reflects the complex process of cancer cell eradication in our patients. We anticipate single cell analysis paired with proteomics to be important future tools for tailor-made therapy in various cancers driven by oncogenic signal transduction.
Chairperson: Rolf K. Reed, CCBIO