Tremendous changes may be seen in current treatment of chronic lymphocytic leukemia (CLL). However, novel therapeutic options require understanding of resistance towards these compounds. We are carrying out research into these central mechanisms of resistance in CLL.
Treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphoma is about to change. Inhibitors against BCL2 (and BTK) replaced classical chemotherapy regimens from first-line settings in CLL. While resistance towards classical chemotherapy was explored over the last decades, resistance mechanisms against novel, non-genotoxic compounds are not understood. Our overarching aims are to i) identify mechanisms of resistance towards BCL2 inhibitors and ii) explore mechanisms that drive disease progression of B- cell lymphoma.
One day, making leukemia a 100 % curable disease for everyone and in every case. – Jose Carreras
The research group’s main aim is to develop targeted, well-tolerated, CTX-free treatments 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.
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.
We identified that resistance towards the BCL2i venetoclax (VEN) in most patients is independent of mutations in the drug target but might be mediated by mutations in BTG1. While BTG1 is an inhibitor of the cell cycle and controls mRNA stability, our preliminary data show that it is involved in expression of BCL2. Our central hypotheses are that the functional loss of BTG1 acts as common molecular determinant of disease progression and (VEN) therapy resistance and affects the pathophysiological BCL2 protein complexes. We identified a deregulation of BCL2 family members such as MCL1, BAX and PUMA. These data point to a complex regulation of resistance mechanisms towards VEN, which raises questions on whether these changes occur at the same time in the same clone, or if each of the changes is sufficient to drive resistance on its own. Therefore, we aim to examine the hierarchy and evolution of intra-tumor events dependent on these changes.
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Kohlhaas V, Blakemore SJ, Al-Maarri M, Nickel N, Pal M, Roth A, Hövelmeyer N, Schäfer SC, Knittel G, Lohneis P, Nikolic M, Wiederstein JL, Franitza M, Georgomonolis T, Reinart N, Herling M, Herling C, Hartmann EM, Rosenwald A, Klapper W, Büttner R, Moia R, Rossi D, Boldorini R, Gaidano G, Frenzel LP, Reinhardt HC, Brüning JC, Hallek M, Krüger M, Peifer M, Pallasch CP, Wunderlich FT. Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. Blood. 2021 Feb 4;137(5):646-660. doi: 10.1182/blood.2020005734. PMID: 33538798.
Riabinska A, Lehrmann D, Jachimowicz RD, Knittel G, Fritz C, Schmitt A, Geyer A, Heneweer C, Wittersheim M, Frenzel LP, Torgovnick A, Wiederstein JL, Wunderlich CM, Ortmann M, Paillard A, Wößmann W, Borkhardt A, Burdach S, Hansmann ML, Rosenwald A, Perner S, Mall G, Klapper W, Merseburg A, Krüger M, Grüll H, Persigehl T, Wunderlich FT, Peifer M, Utermöhlen O, Büttner R, Beleggia F, Reinhardt HC. ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia. 2020 Mar;34(3):771-786. doi: 10.1038/s41375-019-0618-2. Epub 2019 Nov 5. PMID: 31690822.
Weiss J, Peifer M, Herling CD, Frenzel LP, Hallek M. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia (Comment to Tausch et al.). Haematologica. 2019 Nov;104(11):e540. doi: 10.3324/haematol.2019.232835. PMID: 31666345; PMCID: PMC6821598.