Functional identification of drug response and resistance in Richter's Syndrome

里氏综合症药物反应和耐药性的功能鉴定

• 批准号: 10270039
• 负责人: ANTHONY G LETAI
• 金额: $ 29.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270039
• 关键词: Address; Apoptosis; Apoptotic; Appearance; BCL1 Oncogene; BCL2 gene; BH3 peptide; Back; Biological; Biological Assay; Biological Models; Cell Death; Cell model; Cell physiology; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Collaborations; Coupled; Data; Dependence; Dissection; Drug Exposure; Drug Screening; Drug Targeting; Ensure; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family; Funding; Genome; Genomic approach; Genomics; Goals; Human; Individual; Intervention; Learning; Liquid substance; Lymphoma; MCL1 gene; Malignant neoplasm of lung; Maps; Measures; Medical; Methods; Mitochondria; Modeling; Molecular Abnormality; Occupations; Pathology; Patient Rights; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Proteins; Proteomics; Regulation; Resistance; Richter' s Syndrome; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; Specimen; Techniques; Testing; Therapeutic; cancer cell; clinical predictors; companion diagnostics; drug sensitivity; early phase clinical trial; effective therapy; improved; in vivo; inhibitor/antagonist; insight; mimetics; mouse model; mutant; novel; phenome; precision medicine; predicting response; response; small molecule; success; transcriptomics; tumor

Summary (30 lines, broad, long-term) With the advent of more effective therapies in CLL, there is a greater priority on identifying better treatment of Richter's Syndrome (RS), as this has become one of the most important unmet medical needs to address for CLL patients. The main goals of this Project are to utilize functional precision medicine techniques to better understand biological vulnerabilities in Richter's cells and to identify novel pharmacologic interventions to increase apoptotic signaling in these cells. Our priority is on the direct study of viable samples from RS patients obtained in collaboration with the Biospecimens core. We seek to identify the most promising combinations to subsequently explore in early phase clinical trials for patients with RS, funded by other mechanisms. The job of precision medicine is to match the right patient to the right drug. A strategy of genomic sequencing has yielded several successes, such as treating EGFR mutant lung cancer with EGFR inhibitors; however, to date RS has not yielded to the identification of targetable genetic abnormalities, and this will be the focus of Project 1. In Project 3, we propose an alternative approach, which we call functional precision medicine. Rather than rely on static -omic data, we propose to perturb cellular function in ways that allow us to identify active drugs. Central to this strategy is BH3 profiling, a technique in which we expose mitochondria from living cells to synthetic BH3 peptides and measure mitochondrial permeabilization. From this assay we can learn which anti- apoptotic proteins the cell relies on for survival, whether BCL-2, BCL-XL, MCL-1, some combination thereof, or none of these proteins. This information has direct translational application, as clinical BH3 mimetic inhibitors of all three listed proteins now exist. In fact, BH3 profiling was used to direct therapy of the BCL-2 inhibitor venetoclax to CLL and AML, two indications for which venetoclax has now received FDA approval. We propose to use BH3 profiling to identify which BH3 mimetic(s) would be most active in RS. BH3 profiling can also provide a summary measure of how close a cell is to the threshold of apoptosis. When coupled with a brief preceding drug exposure, dynamic BH3 profiling (DBP) can identify drugs from any class that induce apoptotic signaling in cancer cells, moving them closer to the threshold of apoptosis. We have previously demonstrated in several liquid and solid tumor contexts that this strategy accurately identifies drugs with in vivo activity for individual tumors, and can predict clinical response in patients. We propose to use DBP to identify active drugs, after which we will explore their use in combination with each other and with the appropriate BH3 mimetics identified above. As we identify drug vulnerabilities for the panel of RS samples to be studied in this Project, we will compare them with clinical, genomic, transcriptomic, and proteomic annotations prepared by other Projects and Cores in this P01. We hope to use this information to gain insight into the upstream signaling mechanisms that drive drug-induced apoptotic signaling.

摘要（30行，广泛，长期） 随着更有效的 CLL 疗法的出现，确定更好的治疗方法变得更加重要 里氏综合症 (RS)，因为这已成为需要解决的最重要的未满足的医疗需求之一 慢性淋巴细胞白血病患者。该项目的主要目标是利用功能性精准医学技术更好地 了解里克特细胞的生物学脆弱性并确定新的药理学干预措施 增加这些细胞中的凋亡信号传导。我们的首要任务是直接研究来自 RS 患者的活样本 与 Biospecimen 核心合作获得。我们寻求确定最有希望的组合 随后在其他机制的资助下，探索针对 RS 患者的早期临床试验。工作内容 精准医疗的核心就是将正确的患者与正确的药物相匹配。基因组测序策略 取得了多项成功，例如用 EGFR 抑制剂治疗 EGFR 突变型肺癌；然而，迄今为止 RS 尚未识别出可靶向的遗传异常，这将是该项目的重点 1. 在项目3中，我们提出了一种替代方法，我们称之为功能性精准医学。而不是 依靠静态组学数据，我们建议以允许我们识别活性药物的方式扰乱细胞功能。 该策略的核心是 BH3 分析，这是一种我们将活细胞中的线粒体暴露于 合成 BH3 肽并测量线粒体通透性。从这个测定中我们可以了解到哪种抗 细胞赖以生存的凋亡蛋白，无论是 BCL-2、BCL-XL、MCL-1、其某种组合，还是 这些蛋白质都没有。该信息具有直接转化应用，如临床 BH3 模拟抑制剂 所有三种列出的蛋白质现在都存在。事实上，BH3 分析用于指导 BCL-2 抑制剂的治疗 Venetoclax 可用于治疗 CLL 和 AML，这两种适应症 Venetoclax 现已获得 FDA 批准。我们 建议使用 BH3 分析来识别哪些 BH3 模拟物在 RS 中最活跃。 BH3分析可以 还提供了细胞距离凋亡阈值有多近的汇总测量。当与一个 在短暂的药物暴露之前，动态 BH3 分析 (DBP) 可以识别任何类别的药物， 癌细胞中的凋亡信号传导，使它们更接近凋亡阈值。我们之前有过 在几种液体和实体瘤环境中证明，该策略可以准确地识别体内药物 单个肿瘤的活性，并可以预测患者的临床反应。我们建议使用 DBP 来识别 活性药物，之后我们将探索它们之间的组合以及与适当的 BH3 的组合使用 上面确定的模仿者。当我们确定本次研究中要研究的 RS 样本组的药物漏洞时 项目中，我们将它们与由以下人员准备的临床、基因组、转录组和蛋白质组注释进行比较 本 P01 中的其他项目和核心。我们希望利用这些信息来深入了解上游 驱动药物诱导的细胞凋亡信号传导的信号传导机制。