Principal Investigator, CECAD Member
Dr. Lukas Frenzel is carrying out research into the central mechanisms of resistance in chronic lymphatic leukemia (CLL). Together with his team, he wants to identify new targets for overcoming extrinsic apoptosis block and utilizing intrinsic sensitivity to provide targeted, well-tolerated, chemotherapy (CTX)-free treatment, especially for elderly patients with CLL. Such targets for future clinical trials include the mitochondria.
Our research: CLL is the most common form of leukemia in the western world and, so far, remains incurable. Dr. Frenzel and his team are carrying out research into the central mechanisms of resistance in this disease. CLL shows complete resistance to extrinsic apoptosis. On the one hand, it is important to overcome this resistance and, on the other hand, to utilize sensitivity to intrinsic apoptosis in novel treatment concepts. Mitochondria, in particular, represent a meaningful therapeutic target.
Our successes: Starting from the pathological mechanism, the scientists have identified two novel approaches to eliminating CLL cells with CD95 resistance, which are protected by the microenvironment. Their work is based on the previously unknown synergy between two new substances (ABT-199 and ibrutinib), which provides the rationale for future clinical trials.
Our goals: The research group’s main aim is to develop targeted, well-tolerated, CTX-free treatment for patients with CLL.
Dr. Frenzel and his team are therefore looking at ways of overcoming extrinsic resistance to apoptosis and, via the mitochondria, using intrinsic apoptosis mechanisms in a targeted manner to eliminate CLL cells that have lost p53.
Our methods/techniques: Besides targeted mouse models, the team is using biochemical and imaging procedures, such as click chemistry, acyl-biotin exchange assays, and fluorescence lifetime imaging microscopy.
Figure 1: CD95 and APTs interact at the plasma membrane. FLIM-FRET (fluorescence lifetime imaging microscopy to Foerster resonance energy transfer) experiments of CD95 with APT1 and APT2 demonstrate that CD95 directly interacts with both proteins (A). The interaction is dependent on the palmitoylation of cysteine 199 (B).
Berg et al., 2015, Blood.