Targeted Therapies for Richters Transformation

里氏转变的靶向治疗

• 批准号: 10084828
• 负责人: JOHN C. BYRD
• 金额: $ 46.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-07 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084828
• 关键词: Address; Adult; Affect; Animal Model; Automobile Driving; BCL2 gene; Biological; Cancer Relapse; Cell Cycle; Cessation of life; ChIP-seq; Chromatin; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Clonal Evolution; Combined Modality Therapy; Complication; Coupled; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Progression; Enhancers; Epigenetic Process; Event; Face; Gene Expression; Genes; Genetic Transcription; Goals; Hematopoietic Neoplasms; Immunocompetent; In Vitro; Incidence; Individual; Laboratories; Lead; Lesion; Lymphoma; Lymphoma cell; Lymphomagenesis; Malignant Neoplasms; Mediating; Mediator of activation protein; Methyltransferase; Modeling; Natural History; Oncogenes; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Preventive; Prognosis; Proteins; Publishing; Regulation; Resistance; Risk; Risk Factors; Role; Sampling; TP53 gene; Therapeutic; Time; Translating; Translations; Tumor Suppressor Genes; Work; XCL1 gene; c-myc Genes; cancer cell; driver mutation; effective therapy; epigenomics; experimental study; gene repression; genome-wide; high risk; in vivo; in vivo Model; inhibitor/antagonist; innovation; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; leukemia/lymphoma; malignant phenotype; mouse model; neoplastic cell; new therapeutic target; novel; novel marker; novel strategies; novel therapeutic intervention; overexpression; pre-clinical; prevent; programs; protein function; synergism; targeted agent; targeted treatment; therapeutic target; transcriptome sequencing; translational approach; tumor; tumor progression; tumorigenesis; virtual

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.

项目摘要 里希特的转化（RT）是一种侵略性且无法治愈的大型B细胞淋巴瘤（DLBCL） 克隆从慢性淋巴细胞性白血病（CLL）演变，成人最普遍的白血病。患者 开发RT几乎没有治疗选择，尽管有侵略性 多模式疗法。重要的是，RT已成为最常见的疾病进展类型 接受有针对性疗法的CLL患者，例如BTK抑制剂Ibrutinib和Bcl-2抑制剂Venetoclax （ABT-199）。随着这些药物的使用继续增长，抗药性和向RT的发展的出现是 临床关注的越来越多。最近的数据表明，RT是一种生物学和临床上不同的疾病 来自CLL和DLBCL的实体。因此，明确定义的CLL风险因素不能应用于预测 哪些患者将发展RT，表明清晰，未满足的需要确定表观基因组病变的预测 具有最高风险转化风险的患者，并带来真正的治疗方法 这种致命并发症的潜力。 克隆进化被认为是癌症进展和复发的关键特征。大约80-90％的RT案件 尽管驱动RT的机制知之甚少，但源于基础的CLL克隆。目前没有 已经确定了驱动器突变，导致假说，获得的表观遗传病变可能有利于 更具侵略性的RT克隆的出现。大约50％的RT肿瘤显示表观遗传变化 影响CMYC的过表达和p53失活，表明这些途径可能在 Rt的发病机理。 BRD4和PRMT5是我们对P53和C-MYC活性必不可少的表观遗传修饰剂 已显示在几种淋巴瘤模型中具有转化潜力。与执行的CLL患者相反 我们的初步数据不开发RT，表明PRMT5在CLL肿瘤细胞中大量过表达 RT发展前几个月至几年。 PRMT5和BRD4调节的新型目标尚未 在CLL/RT中进行了表征。我们的初步数据支持BRD4-PRMT5-MYC/p53 feed-的存在 驱动RT的恶性表型的正向环，代表一个理想的驱动器轴以提供目标 治疗。该建议将利用一种高度新颖的，集成的表观基因组方法来解决 BRD4和PRMT5如何有助于全球表观遗传变化，有利于RT克隆的出现。 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。此外， 我们生成的创新，自发的，免疫，有能力的RT的鼠模型，加上 新颖的，一流的代理，有选择地靶向BRD4，PRMT5将我们置于独特的位置以制作 通过开发预防和治疗方法，对这种疾病的患者产生重大影响 被翻译成诊所。

项目成果

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.

• DOI: 10.1158/2159-8290.cd-17-0902
• 发表时间: 2018-04
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Ozer HG;El-Gamal D;Powell B;Hing ZA;Blachly JS;Harrington B;Mitchell S;Grieselhuber NR;Williams K;Lai TH;Alinari L;Baiocchi RA;Brinton L;Baskin E;Cannon M;Beaver L;Goettl VM;Lucas DM;Woyach JA;Sampath D;Lehman AM;Yu L;Zhang J;Ma Y;Zhang Y;Spevak W;Shi S;Severson P;Shellooe R;Carias H;Tsang G;Dong K;Ewing T;Marimuthu A;Tantoy C;Walters J;Sanftner L;Rezaei H;Nespi M;Matusow B;Habets G;Ibrahim P;Zhang C;Mathé EA;Bollag G;Byrd JC;Lapalombella R
• 通讯作者: Lapalombella R

Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy.

• DOI: 10.1080/14728222.2018.1474203
• 发表时间: 2018-06
• 期刊: Expert opinion on therapeutic targets
• 影响因子: 5.8
• 作者: Smith E;Zhou W;Shindiapina P;Sif S;Li C;Baiocchi RA
• 通讯作者: Baiocchi RA