Apoptosis Resistance in Cutaneous T Cell Lymphoma: Combination Therapies and Novel Therapeutic Targets

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Cutaneous T cell lymphoma (CTCL) describe a malignant lymphoproliferative disease entity primarily affecting the skin. As no curative therapy has been developed by now, CTCL treatment can only aim at improving symptoms. The therapeutic management of CTCL is often complicated by severe side effects as well as the development of frequent disease relapses. Therefore, there is enormous need for CTCL research in order to improve the management of the disease.In previous basic and clinical research, we developed new therapeutic strategies for CTCL. In collaboration with the National Center of Tumor diseases and the German Cancer Research Center in Heidelberg we identified several aberrant signaling pathways in malignant CTCL cells that can be targeted by medication. These include the transcription factor NFκB and the MAP-Kinase pathway (Brechmann et al.: Immunity 2012; Nicolay et al.: Blood 2016; Kiessling*, Nicolay* et al.: Oncotarget 2017). In addition, we tested medications such as Dimethylfumarat (DMF) and Sorafenib as new therapeutic options for CTCL in vitro and in vivo. We show that DMF inhibits the transcription factor NFκB and Sorafenib interrupts the MAPK signaling pathway. Blocking these pathways successfully restores cell-death sensitivity towards cell death stimuli (Nicolay et al.: Blood 2016; Kiessling*, Nicolay* et al.: Oncotarget 2017) giving rise to options for novel targeted therapy in CTCL.This project proposal bases on these previous data and further augments their insights. First, we investigate Bcl-2 as an additional inhibitor of cell death resistance. To this end, we monitor cell death induction via Bcl-2 in vitro and in vivo and further elucidate the underlying molecular mechanism. Second, we evaluate whether several innovative therapies which inhibit NFκB, MAPK or Bcl-2 show synergistic effects in combination therapies and determine the molecular mechanisms explaining the potential collaborative effect. Third, we compare transcriptomes of CTCL cells from patient collectives with different therapies and clinical courses in order to identify whether the specific therapies induce different alterations in gene expression that can potentially be addressed by combination therapy. To sum up, the objective of this proposal is to use established methods like cell-death essays, nucleic acid and protein functional essays as well as new sequencing techniques to identify new specific therapeutic options for CTCL. Due to their specificity on malignant cells, these options should be characterized by a higher efficacy and milder side effects than existing therapies.