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

皮肤 T 细胞淋巴瘤的细胞凋亡抵抗：联合疗法和新的治疗靶点

• 批准号: 398461835
• 负责人: Professor Dr. Jan P. Nicolay
• 金额: --
• 依托单位: Klinik für Dermatologie, Venerologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398461835?language=en
• 关键词: Apoptosis; Resistance; Cutaneous; Cell; Lymphoma

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.

皮肤T细胞淋巴瘤（CTCL）是一种主要影响皮肤的恶性淋巴细胞增生性疾病。由于目前尚无有效的治疗方法，CTCL治疗只能以改善症状为目的。CTCL的治疗管理往往因严重的副作用以及频繁的疾病复发而复杂化。因此，迫切需要对CTCL进行研究，以改善疾病的管理。在之前的基础和临床研究中，我们开发了新的治疗策略。在与国家肿瘤疾病中心和海德堡德国癌症研究中心的合作中，我们在恶性CTCL细胞中发现了几种可以通过药物靶向的异常信号通路。其中包括转录因子NFκB和map -激酶途径（Brechmann等人：Immunity 2012； Nicolay等人：Blood 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CTCL的新治疗选择。我们发现DMF抑制转录因子NFκB，索拉非尼阻断MAPK信号通路。阻断这些通路可以成功恢复细胞对死亡刺激的敏感性（Nicolay et al.: Blood 2016; Kiessling*, Nicolay* et al.: Oncotarget 2017），为CTCL的新型靶向治疗提供了选择。本项目提案以这些先前的数据为基础，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剂。为此，我们在体外和体内监测Bcl-2诱导细胞死亡的情况，并进一步阐明其潜在的分子机制。其次，我们评估了几种抑制NFκB、MAPK或Bcl-2的创新疗法是否在联合治疗中表现出协同效应，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过程的CTCL患者群体的转录组，以确定特定治疗是否会诱导基因表达的不同改变，这些改变可能通过联合治疗来解决。综上所述，本提案的目的是利用细胞死亡论文、核酸和蛋白质功能论文等现有方法以及新的测序技术来确定CTCL的新的特异性治疗方案。由于它们对恶性细胞的特异性，这些选择应该具有比现有疗法更高的疗效和更轻的副作用。