Reading mitochondrial apoptotic signaling to identify active cancer therapeutics

读取线粒体凋亡信号以识别活性癌症疗法

• 批准号: 9816344
• 负责人: ANTHONY G LETAI
• 金额: $ 81.02万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9816344
• 关键词: Acute Myelocytic Leukemia; Apoptosis; Apoptotic; BCL2 gene; BH3 Domain; BH3 peptide; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinic; Clinical Trials; Disease; Disease remission; Drug usage; Family; Hour; Immunooncology; Laboratories; Liquid substance; Malignant Neoplasms; Measures; Mitochondria; Non-Malignant; Oligopeptides; Oncologist; Outer Mitochondrial Membrane; Pharmaceutical Preparations; Phenotype; Protein Family; Proteins; Reading; Signal Transduction; Solid; Solid Neoplasm; Somatic Cell; Supervision; Therapeutic; Therapeutic Index; base; cancer cell; cancer type; cell suicide; chemotherapy; design; drug sensitivity; human model; in vivo; inhibitor/antagonist; interest; mouse model; neoplastic cell; novel therapeutics; peptide I; predictive marker; pro-apoptotic protein; programs; small molecule inhibitor; success; tool; tumor

Summary I am an oncologist and cancer biologist supervising a laboratory focused on identifying therapies that selectively induce apoptosis in cancer cells. My initial contributions to the apoptosis field came with separating certain pro-death BCL-2 family BH3-only proteins into “sensitizers” and “activators” based on pro-apoptotic function. This finding drove my interest in the possibilities of inhibiting BCL-2 function with drugs that mimicked the BH3 domain of pro-apoptotic proteins. I designed the first mouse model that demonstrated that loss of BCL-2 function by itself could be sufficient to drive a cancer into remission. Following this, I designed a tool called BH3 profiling – exposing mitochondria to synthetic oligo-peptides based on the amphipathic alpha- helical BH3 domains of proapoptotic proteins and measuring mitochondrial outer membrane permeabilization (MOMP). By using certain selectively-interacting BH3 peptides, I could use BH3 profiling to identify cells that were especially sensitive to BH3 inhibition. I used BH3 profiling to help launch clinical trial programs of the BCL-2 inhibitor venetoclax in several diseases. Most successful among these so far have been programs in chronic lymphocytic leukemia and acute myelogenous leukemia, the former of which has already yielded FDA approvals. Using different BH3 peptides, BH3 profiling can measure overall apoptotic priming, or proximity to the threshold of apoptosis. We used this aspect to demonstrate that differential apoptotic priming is perhaps the most significant determinant of successful chemotherapy treatment. Moreover, differential apoptotic priming is the main reason that there is a therapeutic index for conventional chemotherapy – most non-malignant somatic cells are far less primed for apoptosis than chemosensitive cancer cells. Building on this finding, we asked whether we could identify drugs that could enhance apoptotic priming selectively in cancer cells. We found that we could measure increased apoptotic priming within hours of exposing cancer cells to effective drugs using dynamic BH3 profiling (DBP). Increased priming is measured as increased sensitivity of mitochondria in treated cells to BH3 peptides compared to untreated controls. Over the past few years, we have found that an increased priming by a drug in DBP is an excellent predictor of in vivo activity in human and mouse models, in solid and liquid tumors. An important advantage of DBP over most other ex vivo drug sensitivity strategies is that DBP requires no more than 24 hours of ex vivo culture. This overcomes the major obstacle to the general application of such strategies, since many cancers cannot adapt to long-term ex vivo culture, and if they do, they are phenotypically altered so as to degrade the information they can provide. We are exploring DBP as a discovery tool and predictive biomarker in many liquid and solid tumors. Moreover, we are using it as a tool to identify drugs that can make target tumor cells more sensitive to immuno-oncology therapies.

概括 我是一名肿瘤学家和癌症生物学家，负责监督一个实验室，该实验室专注于识别以下疗法： 选择性诱导癌细胞凋亡 我对细胞凋亡领域的最初贡献来自于分离。 将某些促死亡 BCL-2 家族 BH3-only 蛋白转化为基于促凋亡的“敏化剂”和“激活剂” 这一发现激发了我对用类似药物抑制 BCL-2 功能的可能性的兴趣。 我设计了第一个小鼠模型，证明了促凋亡蛋白的 BH3 结构域的缺失。 BCL-2 功能本身就足以使癌症缓解。在此之后，我设计了一个工具。 称为 BH3 分析 - 将线粒体暴露于基于两亲性 α- 的合成寡肽 促凋亡蛋白的螺旋 BH3 结构域和测量线粒体外膜通透性 (MOMP) 通过使用某些选择性相互作用的 BH3 肽，我可以使用 BH3 分析来识别细胞 对 BH3 抑制特别敏感，我使用 BH3 分析来帮助启动该药物的临床试验计划。 BCL-2 抑制剂 Venetoclax 在多种疾病中的应用迄今为止最为成功。 慢性淋巴细胞白血病和急性粒细胞白血病，前者已获得 FDA 批准 批准。 使用不同的 BH3 肽，BH3 分析可以测量整体细胞凋亡启动或接近阈值 我们用这个方面来证明差异性细胞凋亡启动可能是最重要的。 此外，不同的细胞凋亡启动是化疗成功的重要决定因素。 常规化疗有治疗指数的主要原因——大多数非恶性躯体细胞 基于这一发现，我们询问细胞凋亡的准备程度远低于化学敏感的癌细胞。 我们发现是否可以找到能够选择性增强癌细胞凋亡的药物。 我们可以在将癌细胞暴露于有效药物的数小时内测量细胞凋亡启动的增加 使用动态 BH3 分析 (DBP) 来测量启动的增加，即线粒体敏感性的增加。 与未处理的对照相比，经过 BH3 肽处理的细胞在过去几年中发现 DBP 中药物引发的增加是人和小鼠模型中体内活性的极好预测因子， 与大多数其他体外药物敏感性策略相比，DBP 的一个重要优势是实体和液体肿瘤。 DBP需要不超过24小时的离体培养，这克服了一般的主要障碍。 应用此类策略，因为许多癌症无法适应长期离体培养，如果适应的话， 它们的表型被改变，从而降低了它们可以提供的信息，我们正在探索 DBP 作为一种药物。 此外，我们将其用作许多液体和实体肿瘤的发现工具和预测生物标志物。 确定可以使靶肿瘤细胞对免疫肿瘤疗法更加敏感的药物。