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: 10491151
• 负责人: ANTHONY G LETAI
• 金额: $ 28.55万
• 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/10491151
• 关键词: Address; Apoptosis; Apoptotic; Appearance; BCL1 Oncogene; BCL2 gene; BCL2L1 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; insight; mimetics; mouse model; mutant; novel; phenome; precision medicine; predicting response; response; small molecule; success; transcriptomics; translational applications; 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，宽，长期） 随着CLL中更有效疗法的出现，确定更好的治疗 里希特综合症（RS），因为这已成为最重要的未满足医疗需求之一 CLL患者。该项目的主要目标是利用功能性精确医学技术来改善 了解Richter细胞中的生物学脆弱性，并确定新颖的药理学干预措施 增加这些细胞中的凋亡信号传导。我们的优先级是直接研究RS患者的可行样品 与Biospimens Core合作获得。我们试图确定最有希望的组合 随后，在早期临床试验中针对Rs患者进行的临床试验，并由其他机制资助。工作 精确药物是将正确的患者与正确的药物相匹配。基因组测序的策略具有 取得了一些成功，例如用EGFR抑制剂治疗EGFR突变肺癌；但是，迄今为止 RS尚未屈服于识别可靶向遗传异常，这将是项目的重点 1。在项目3中，我们提出了一种替代方法，我们称之为功能精确医学。而不是 依靠静态数据，我们建议以使我们能够识别活性药物的方式扰动细胞功能。 该策略的核心是BH3分析，该技术使我们将线粒体从活细胞暴露到 合成BH3肽并测量线粒体通透性。通过此测定，我们可以了解哪种反 凋亡蛋白细胞依赖于生存，无论是Bcl-2，Bcl-XL，Mcl-1，其某种组合还是 这些蛋白质都不是。该信息具有直接的转化应用，作为临床BH3模拟抑制剂 现在存在三种列出的蛋白质中。实际上，BH3分析用于直接治疗Bcl-2抑制剂 Venetoclax到CLL和AML，Venetoclax现在已获得FDA批准的两个迹象。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 还提供了一个摘要量度，以衡量细胞与凋亡阈值的距离。当与 在药物暴露之前的简短，动态BH3分析（DBP）可以从任何诱导的类中识别药物 癌细胞中的凋亡信号传导，使其更接近凋亡的阈值。我们以前有 在几种液体和实体肿瘤的情况下证明了该策略可以准确地识别出体内的药物 单个肿瘤的活性，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，我们将探索它们与彼此组合的使用以及适当的BH3 上面确定的模拟物。当我们确定了在此研究的RS样品小组的药物漏洞时 项目，我们将将它们与临床，基因组，转录组和蛋白质组学注释进行比较 该P01中的其他项目和核心。我们希望使用这些信息来深入了解上游 信号传导机制驱动药物引起的凋亡信号传导。