Targeted Therapies for Richters Transformation

项目摘要 里希特变换(RT)是一种侵袭性和不可治愈的弥漫性大B细胞淋巴瘤(DLBCL)， 克隆性由慢性淋巴细胞白血病(CLL)进化而来，慢性淋巴细胞白血病是成人最常见的白血病。患者 发展RT几乎没有治疗选择，尽管具有侵略性，但面临只有6-8个月的严峻预后 多模式治疗。重要的是，RT已经成为最常见的疾病进展类型 接受靶向治疗的慢性淋巴细胞性白血病患者，如BTK抑制剂伊布鲁替尼和Bcl-2抑制剂万乃克莱 (ABT-199)。随着这些药物的使用不断增加，出现了对RT的耐药性和进展 引起越来越多的临床关注。最近的数据表明，RT是一种生物学和临床上截然不同的疾病。 来自CLL和DLBCL的实体。正因为如此，明确定义的慢性淋巴细胞性白血病的风险因素不能用于预测 哪些患者将发生RT，表明明确的、未得到满足的需求，以识别预测表观基因组病变的 具有最高转化风险的患者，并提出具有真正疗效的新治疗方案 有可能出现这种致命的并发症。 克隆进化被认为是癌症进展和复发的关键特征。约80%-90%的RT病例 起源于潜在的CLL克隆，尽管驱动RT的机制尚不清楚。目前没有 已经发现了驱动基因突变，这导致了一种假设，即获得性表观遗传损害可能有利于 出现了更具侵略性的RT克隆。大约50%的RT肿瘤表现为表观遗传学变化 影响cMYC过表达和P53失活，提示这些途径可能在 RT的发病机制。BRD4和PRMT5是对p53和c-myc活性至关重要的表观遗传修饰物，我们 在几种淋巴瘤模型中都显示出转化的潜力。与CLL患者不同的是 不发展RT，我们的初步数据显示PRMT5在CLL肿瘤细胞中大量过表达 比RT的发展早几个月到几年。PRMT5和BRD4调控的新靶点都没有 已在CLL/RT中进行了表征。我们的初步数据支持BRD4-PRMT5-MYC/P53馈送的存在- 驱动RT恶性表型的前向环，代表了理想的驱动器轴，以提供有针对性的 心理治疗。该提案将利用一种高度新颖的、集成的表观基因组学方法来机械地解决 BRD4和PRMT5如何促进有利于RT克隆出现的全球表观遗传学变化。 如果成功，我们的实验将确定与RT风险相关的独特的表观基因组疾病。另外， 利用我们产生的创新的、自发的、免疫能力强的RT小鼠模型与 新型、一流的代理选择性地针对BRD4和PRMT5，使我们处于独特的地位，可以 通过开发预防和治疗方法对患有这种疾病的患者产生重大影响 被转送到诊所。

Project Summary Richter's transformation (RT) is an aggressive and incurable diffuse large B cell lymphoma (DLBCL) that clonally evolves from chronic lymphocytic leukemia (CLL), the most prevalent leukemia in adults. Patients who develop RT have few treatment options and face a grim prognosis of only 6-8 months despite aggressive multimodal therapy. Importantly, RT has become the most common type of disease progression observed in CLL patients receiving targeted therapies such as the BTK inhibitor Ibrutinib and the Bcl-2 inhibitor Venetoclax (ABT-199). As the use of these agents continues to grow, emergence of resistance and progression to RT are of increasing clinical concern. Recent data suggests that RT is a biologically and clinically distinct disease entity from CLL and DLBCL. Because of this, well-defined risk factors for CLL cannot be applied to predict which patients will develop RT, indicating clear, unmet needs to identify epigenomic lesions predictive of patients at the highest risk for transformation and to bring forward novel treatment options with real curative potential for this fatal complication. Clonal evolution is considered a key feature of cancer progression and relapse. About 80-90% of RT cases arise from the underlying CLL clone although the mechanisms driving RT are poorly understood. Currently no driver mutations have been identified leading to the hypothesis that acquired epigenetic lesions may favor the emergence of the more aggressive RT clone. Approximately 50% of RT tumors display epigenetic changes affecting cMYC over-expression and P53 inactivation, suggesting these pathways may play a major role in the pathogenesis of RT. BRD4 and PRMT5 are epigenetic modifiers essential for P53 and c-MYC activity that we have shown to have transforming potential in several lymphoma models. In contrast to CLL patients who do not develop RT, our preliminary data show that PRMT5 is abundantly over-expressed in CLL tumor cells months to years prior the development of RT. Novel targets of both PRMT5 and BRD4 regulation have not been characterized in CLL/RT. Our preliminary data supports the existence of a BRD4-PRMT5-MYC/P53 feed- forward loop that drives the malignant phenotype of RT and represents an ideal driver axis to deliver targeted therapy. This proposal will utilize a highly novel, integrated epigenomic approach to mechanistically address how BRD4 and PRMT5 contribute toward global epigenetic changes favoring the emergence of the RT clone. If successful our experiments will identify unique epigenomic disease associated with risk of RT. Additionally, the use of innovative, spontaneous, immune competent murine models of RT we have generated coupled with novel, first-in-class agents that selectively target BRD4 and PRMT5 place us in a unique position to make a significant impact for patients with this disease by developing preventive and therapeutic approaches that can be translated into the clinic.