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

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，如伊鲁替尼、理想拉利布或维尼托克拉克斯，靶向特定途径，并显示出令人印象深刻和持久的反应。当这些新型药物与抗体联合使用时，可能很快就会完全取代CLL的化疗。然而，尽管取得了这些令人印象深刻的进展，仍然存在一个非常相关的临床问题：基因定义的高风险患者对这些药物的耐药性。具体来说，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。除了之前发现的不同DDR基因的缺陷外，影响NFkB-、KRAS/MAPK-和PI3K/AKT通路、B细胞受体（BCR）和toll样受体（TLR）信号通路以及RNA代谢和剪接机制的改变最近也被认为是CLL的高风险畸变。在第一个资助期内产生的工具的基础上，拟议的项目旨在确定与CLL细胞中功能受损的DDR相关的可治疗性分子脆弱性。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治疗CLL。cru286受益于其成员的互补性专业知识。在这个CRU中发现或表征了几个参与DDR信号传导或影响DNA损伤的细胞结果的分子。我们进一步受益于一系列相关的体内模型来研究CLL生物学的关键途径。除了已有的专业知识外，我们还战略性地招募了两个额外的团队，涵盖之前在我们的联盟中未被充分代表的高度相关方面，即表观遗传学和通过SF3B1突变介导的错误调节剪接（RP8），以及系统的体外和体内药物筛选，重点是靶向cll特异性凋亡机制缺陷（RP7）。此外，我们将重点关注CLL的分子进化。我们通过招募M. Peifer对我们的生物信息基础设施进行了大量投资，他对人类恶性肿瘤的克隆进化有着长期的兴趣。CLL几乎是一种理想的疾病，因为通过简单的静脉切开术可以很容易地获得肿瘤样本，而且CLL通常是一种缓慢增殖的疾病，这使得可以在很长一段时间内观察受影响的个体，并在多个不同的治疗路线中进行观察。

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.