Targeted Therapies for Richters Transformation

项目摘要 里希特转化（RT）是一种侵袭性和不可治愈的弥漫性大B细胞淋巴瘤（DLBCL）， 慢性淋巴细胞性白血病（CLL）是成人中最普遍的白血病。的患者 患有RT的患者几乎没有治疗选择，尽管积极治疗，但只有6-8个月的严峻预后。 多模式治疗重要的是，RT已成为在糖尿病患者中观察到的最常见的疾病进展类型。 接受BTK抑制剂伊布替尼和Bcl-2抑制剂维奈托克等靶向治疗的CLL患者 （ABT-199）。随着这些药物的使用持续增长，耐药性的出现和对RT的进展也在增加。 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不同的疾病 CLL和DLBCL的实体。因此，明确定义的CLL风险因素不能用于预测 哪些患者将发展RT，表明明确的，未满足的需求，以确定表观基因组病变预测 转化风险最高的患者，并提出具有真实的治愈性的新治疗方案。 这种致命并发症的可能性。 克隆演变被认为是癌症进展和复发的关键特征。大约80-90%的RT病例 从潜在的CLL克隆中产生，尽管驱动RT的机制知之甚少。目前没有 已经确定了驱动突变，导致获得性表观遗传病变可能有利于 更有侵略性的RT克隆的出现。大约50%的RT肿瘤显示表观遗传学变化 影响cMYC的过度表达和P53的失活，这表明这些途径可能在细胞凋亡中起主要作用。 BRD 4和PRMT 5是P53和c-MYC活性所必需的表观遗传修饰剂， 已经显示在几种淋巴瘤模型中具有转化潜力。与CLL患者相比， 我们的初步数据显示PRMT 5在CLL肿瘤细胞中大量过表达， PRMT 5和BRD 4调节的新靶点尚未被发现。 我们的初步数据支持BRD 4-PRMT 5-MYC/P53补料的存在， 前向环驱动RT的恶性表型，代表了理想的驱动轴， 疗法该提案将利用一种高度新颖的、整合的表观基因组方法来机械地解决 BRD 4和PRMT 5如何促进有利于RT克隆出现的全局表观遗传变化。 如果成功，我们的实验将确定与RT风险相关的独特表观基因组疾病。 使用创新的，自发的，免疫能力强的鼠RT模型，我们已经产生了结合 选择性靶向BRD 4和PRMT 5的新型一流药物使我们处于独特的地位， 通过开发预防和治疗方法， 翻译到诊所。

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.