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

皮肤T细胞淋巴瘤(CTCL)是一种主要影响皮肤的恶性淋巴增生性疾病。由于目前还没有根治方法，CTCL的治疗只能以改善症状为目的。CTCL的治疗常常因严重的副作用和频繁的疾病复发而变得复杂。因此，对于CTCL的研究是非常有必要的，以改善对疾病的管理。在以往的基础和临床研究中，我们开发了CTCL的新的治疗策略。在与国家肿瘤疾病中心和位于海德堡的德国癌症研究中心的合作下，我们在恶性CTCL细胞中发现了几个可以被药物靶向的异常信号通路。其中包括转录因子NFκB和MAP-Kinase途径(Brechmann等人：免疫2012年；Nicolay等人：血液2016；Kiessling*，Nicolay*等人：OncoTarget 2017)。此外，我们在体外和体内测试了富马酸二甲酯(DMF)和索拉非尼等药物作为治疗CTCL的新选择。我们发现二甲基甲酰胺抑制转录因子NFAPKB，索拉非尼阻断κ信号通路。阻断这些途径成功地恢复了细胞死亡对细胞死亡刺激的敏感性(Nicolay等人：血液2016；Kiessling*，Nicolay*等人：OncoTarget 2017)，从而产生了CTCL新的靶向治疗的选择。本项目提案基于这些先前的数据，并进一步增强了他们的见解。首先，我们研究了Bcl-2作为细胞死亡抵抗的额外抑制因子。为此，我们在体内外监测了Bcl2诱导的细胞死亡，并进一步阐明了其潜在的分子机制。其次，我们评估了几种抑制NF-κB、MAPK或Bcl2的创新疗法在联合疗法中是否显示出协同效应，并确定了解释潜在协同效应的分子机制。第三，我们比较了不同治疗方法和临床病程的患者组的CTCL细胞的转录，以确定特定的治疗是否会导致基因表达的不同变化，这些变化可能可以通过联合治疗来解决。综上所述，这项建议的目标是使用已有的方法，如细胞死亡论文、核酸和蛋白质功能论文以及新的测序技术来确定CTCL的新的特定治疗方案。由于它们对恶性细胞的特异性，这些选择的特点是比现有的治疗方法具有更高的疗效和更温和的副作用。

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.