B2: Genomic and epigenetic mechanisms of resistance and Richter transformation in CLL patients treated with novel compounds

Principal investigators

PD Dr. rer. nat. Daniel Mertens
Department of Internal Medicine III
Albert-Einstein-Allee 23
89081 Ulm
Phone: 0731-500-45870
daniel.mertens(at)uniklinik-ulm.de

Curriculum Vitae

Prof. Dr. med. Hartmut Döhner
Department of Internal Medicine III
Albert-Einstein-Allee 23
89081 Ulm
Phone: 0731-500-45501
hartmut.doehner(at)uniklinik-ulm.de

Curriculum Vitae

Prof. Dr. med. Stephan Stilgenbauer
Department of Internal Medicine III
Albert-Einstein-Allee 23
89081 Ulm
Phone: 0731-500-45521
stephan.stilgenbauer(at)uniklinik-ulm.de

Curriculum Vitae

Summary

With ibrutinib, idelalisib and venetoclax, novel target-specific compounds are currently revolutionizing CLL treatment. Although the efficacy of these drugs is remarkable, refractoriness to treatment occurs in a subset of 15-30% of these patients after 2-3 years, and many of them suffer transformation to Richter syndrome. As specific genomic alterations may predict outcome in patients during therapy with targeted agents, we seek to identify specific resistance mechanisms based on gene mutations, copy number variations and epigenetic aberration patterns for each patient at baseline and at progression time point using our estab-lished pipelines. In addition to CLL progression, Richter transformation (aggressive lymphoma arising in a CLL patient) is one of the major resistance mechanisms to novel compounds. For most of these patients, sequential CLL samples during treatment were obtained and will provide evidence of the underlying transi-tion to aggressive lymphoma. Once mutations or specific expression patters associated with refractoriness are identified, we will explore their mechanistic connection to the molecular mode of action of the specific compound. This will include functional assays on i) viably frozen cells of affected patients, and ii) in vitro (cell lines) models after induced resistance via CRISPR/Cas and shRNA knockdown. The results of our ap-proach will serve as a basis to overcome resistance by drug modification or combination treatment as well as a basis for “precision medicine”.

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