Developing a new therapy for leukemia

Research groups led by Dr. Tilman Brummer and Prof. Dr. Jörn Dengjel from the Cluster of Excellence BIOSS Centre for Biological Signalling Studies of the University of Freiburg will receive a total of just under 200,000 euros in funding from the José Carreras Leukemia Foundation in the coming two years. The two teams, which are also affiliated with the Institute of Molecular Medicine and Cell Research and the Department of Dermatology of the University of Freiburg, aim to study what role the Gab2 docking protein plays under the influence of new drugs currently being used in clinical practice.

The research will focus on so-called tyrosine-kinase inhibitors (TKI). Tyrosine kinases are proteins that have been modified by mutations in the cancer cells and thus constantly send growth signals. One mutated tumor cell-specific tyrosine kinase of this kind is Bcr-Abl, which is present in 95 percent of all cases of chronic myeloid leukemia (CML). TKIs developed to combat Bcr-Abl have radically changed the face of therapy in the past 15 years, as they specifically inhibit the impaired signaling in the leukemia cells. This has enabled the development of a targeted therapy that exhibits less side-effects than conventional chemotherapies. However, these TKIs only take effect in 75 percent of CML patients. Many forms of leukemia develop a resistance to this these targeted therapies in the long term. It is thus imperative to study the causes of this primary and secondary therapy resistance.

In this connection, Brummer’s team has recently shown that the Gab2 docking protein influences the effectiveness of TKIs in CML cells. In her dissertation, which she wrote in close cooperation with the Institute of Pathology and the Department of Medicine I of the Medical Center – University of Freiburg, Franziska Wöhrle from Brummer’s research group verified that a high amount of Gab2 proteins protects CML cells from TKIs. A reduction of Gab2 proteins in CML cells, on the other hand, increases the effectiveness of TKIs. These findings indicate that Gab2 could be a promising point of departure for new therapies.

In order to better understand what mechanisms Gab2 uses to reduce the effectiveness of TKIs in CML and other forms of myeloid leukemia, the two research groups have begun to investigate the influence of TKIs on the Gab2 protein with the help of so-called phospho-proteomic analyses. Initial data show that imatinib and dasatinib, TKIs often used in clinical practice, influence the Gab2 protein in different ways. Now the researchers want to expand on the study and investigate further TKIs with relevance for clinical practice.