KFO 286: Exploiting Defects in the DNA Damage Response for the Treatment of Chronic Lymphocytic Leukemia

KFO 286：利用 DNA 损伤反应的缺陷来治疗慢性淋巴细胞白血病

• 批准号: 226262100
• 金额: --
• 依托单位: Max-Planck-Institut für Stoffwechselforschung
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226262100?language=en
• 关键词: KFO; 286; Exploiting; Defects; DNA

Treatment of chronic lymphocytic leukemia (CLL) is currently undergoing fundamental changes. Novel agents with limited toxicity, such as ibrutinib, idelalisib or venetoclax, target specific pathways and show impressive and durable responses. These novel agents, when used in combination with antibodies may soon completely replace chemotherapy for CLL. However, despite this impressive progress, there remains a very relevant clinical problem: resistance to these agents in genetically-defined high-risk patients. Specifically, resistance to chemotherapy and novel, targeted agents is tightly correlated with molecular defects in the DNA damage response (DDR). In addition to the previously identified defects in different DDR genes, alterations affecting the NFkB-, KRAS/MAPK- and PI3K/AKT pathways, B cell receptor (BCR)- and Toll-like receptor (TLR) signaling, as well as RNA metabolism and the splicing machinery, have recently emerged as high-risk aberrations in CLL.Building on the tools generated within the first funding period, the proposed projects aim at identifying therapeutically actionable molecular vulnerabilities associated with a functionally impaired DDR in CLL cells. Our results will enhance our understanding of CLL pathogenesis and will lead to the development of novel therapeutic approaches to tackle CLL. The CRU-286 benefits from the complementary expertise of its members. Several molecules involved in DDR signaling, or impacting on cellular outcomes upon DNA damage, were discovered or characterized within this CRU. We further benefit from a range of relevant in vivo models to study key pathways in CLL biology. Beyond the pre-existing expertise, we have strategically recruited two additional groups covering highly relevant aspects that were previously underrepresented in our consortium, namely epigenetics and mis-regulated splicing mediated through SF3B1 mutations (RP8), as well as systematic in vitro and in vivo drug screening, with a focus on targeting CLL-specific defects in the apoptotic machinery (RP7). In addition, we will focus on the molecular evolution of CLL. We have substantially invested into our bioinformatic infrastructure through the recruitment of M. Peifer, who has a longstanding interest in the clonal evolution of human malignancies. CLL is an almost ideal disease for this purpose, as tumor samples are easily accessible through simple phlebotomy and due to the fact that CLL is often a slowly proliferating disease, which allows the observation of affected individuals over a long period of time and during the course of multiple distinct lines of treatment.

慢性淋巴细胞白血病（CLL）的治疗目前正在发生根本性的变化。具有有限毒性的新型药物，如伊曲替尼、艾代拉里斯或维奈托克，靶向特定的途径，并显示出令人印象深刻和持久的反应。这些新的药物，当与抗体联合使用时，可能很快就会完全取代CLL的化疗。然而，尽管取得了令人印象深刻的进展，但仍然存在一个非常相关的临床问题：遗传学定义的高风险患者对这些药物的耐药性。具体而言，对化疗和新型靶向药物的耐药性与DNA损伤反应（DDR）中的分子缺陷密切相关。除了先前在不同DDR基因中鉴定的缺陷之外，影响NF κ B-、KRAS/MAPK-和PI 3 K/AKT通路、B细胞受体（BCR）-和Toll样受体（TLR）信号传导以及RNA代谢和剪接机制的改变最近已成为CLL中的高风险畸变。所提出的项目旨在鉴定与CLL细胞中功能受损的DDR相关的治疗上可行的分子弱点。我们的研究结果将增强我们对CLL发病机制的理解，并将导致开发新的治疗方法来解决CLL。CRU-286受益于其成员的互补专业知识。在该CRU中发现或表征了参与DDR信号传导或影响DNA损伤后细胞结果的几种分子。我们进一步受益于一系列相关的体内模型，以研究CLL生物学中的关键途径。除了现有的专业知识，我们还战略性地招募了另外两个小组，涵盖了以前在我们的联盟中代表性不足的高度相关方面，即表观遗传学和通过SF 3B 1突变介导的错误调节剪接（RP 8），以及系统的体外和体内药物筛选，重点是靶向细胞凋亡机制中的CLL特异性缺陷（RP 7）。此外，我们将重点关注CLL的分子进化。我们通过招募M.他对人类恶性肿瘤的克隆进化有着长期的兴趣。CLL是用于此目的的几乎理想的疾病，因为肿瘤样品通过简单的静脉切开术容易获得，并且由于CLL通常是缓慢增殖的疾病，这允许在长时间内和在多个不同的治疗线的过程中观察受影响的个体。

项目成果

The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression.

Cdkn1aSUPER 小鼠作为研究 p53 介导的肿瘤抑制的工具

• DOI: 10.1016/j.celrep.2018.09.079
• 发表时间: 2018
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Torgovnick A;Heger JM;Liaki V;Isensee J;Schmitt A;Knittel G;Riabinska A;Beleggia F;Laurien L;Leeser U;Jungst C;Siedek F;Vogel W;Klumper N;Nolte H;Wittersheim M;Tharun L;Castiglione R;Kruger M;Schauss A;Perner S;Pasparakis M;Buttner R
• 通讯作者: Buttner R

Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

• DOI: 10.1038/s41586-019-1770-6
• 发表时间: 2019-11-28
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Fritsch, Melanie;Gunther, Saskia D.;Kashkar, Hamid
• 通讯作者: Kashkar, Hamid

The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL

• DOI: 10.1038/leu.2015.114
• 发表时间: 2015-05
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Elena Vasyutina;Jorge Bouças;J. Bloehdorn;C. Aszyk;G. Crispatzu;Marius Stiefelhagen;A. Breuer;Petra Mayer;Claudia Lengerke;Hartmut Döhner;Dirk Beutner;Andreas Rosenwald;S. Stilgenbauer;Michael Hallek;A. Benner;Marco Herling

Reinstated p53 response and high anti-T-cell leukemia activity by the novel alkylating deacetylase inhibitor tinostamustine

• DOI: 10.1038/s41375-020-0772-6
• 发表时间: 2020-02
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: S. Pützer;L. Varghese;J. von Jan;T. Braun;A. Giri;P. Mayer;N. Riet;S. Timonen;S. Oberbeck;H. Kuusanmäki;S. Mustjoki;M. Stern;T. Aittokallio;S. Newrzela;A. Schrader;M. Herling

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

• DOI: 10.1038/s41467-017-02688-6
• 发表时间: 2018-02-15
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Schrader，A.;Crispatzu，G.;Herling，M.
• 通讯作者: Herling，M.