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: 10669581
• 负责人: ANTHONY G LETAI
• 金额: $ 101.62万
• 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/10669581
• 关键词: Acute Myelocytic Leukemia; Amphipathic Alpha Helix; Apoptosis; Apoptotic; BCL1 Oncogene; BH3 Domain; BH3 peptide; Cell Membrane Permeability; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinic; Clinical Trials; Disease; Disease remission; Drug usage; Family; Hour; Immunooncology; Induction of Apoptosis; 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; Therapeutic; Therapeutic Index; cancer cell; cancer type; cell suicide; chemotherapy; design; drug sensitivity; human model; in vivo; inhibitor; interest; mouse model; neoplastic cell; novel therapeutics; 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 我是一名肿瘤科医生和癌症生物学家，负责识别疗法的实验室 有选择地诱导癌细胞凋亡。我对凋亡领域的最初贡献是分开的 基于促凋亡 功能。这一发现引起了我对抑制bcl-2功能的可能性的兴趣 促凋亡蛋白的BH3结构域。我设计了第一个鼠标模型，证明了丢失 Bcl-2功能本身可能足以使癌症缓解。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）。通过使用某些有选择性相互作用的BH3 Pepperides，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分析来帮助启动临床试验计划 Bcl-2抑制剂Venetoclax在几种疾病中。到目前为止，最成功的是计划 慢性淋巴细胞性白血病和急性骨髓性白血病，前者已经产生FDA 批准。 使用不同的BH3肽，BH3分析可以测量整体凋亡启动或距阈值 凋亡。我们利用这方面证明差异凋亡启动可能是最大的 成功化疗治疗的重要决定因素。此外，差异凋亡启动是 常规化学疗法有治疗指数的主要原因 - 大多数非机敏的体细胞 与化学敏感性癌细胞相比，细胞对凋亡的启动要小得多。在这一发现的基础上，我们问 我们是否可以鉴定可以在癌细胞中选择性地增强凋亡启动的药物。我们发现 我们可以在将癌细胞暴露于有效药物的数小时内测量凋亡的增加 使用动态BH3分析（DBP）。启动的增加是用线粒体在 与未处理的对照相比，已处理过BH3辣椒的细胞。在过去的几年中，我们发现 DBP中药物的启动增加是人体和小鼠模型中体内活性的极好预测指标， 固体和液体肿瘤。与大多数其他离体药物敏感性策略相比，DBP的重要优势是 该DBP不需要超过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的离体文化，如果他们这样做， 它们是表型改变的，以降低它们可以提供的信息。我们正在探索DBP 许多液体和实体瘤中的发现工具和预测性生物标志物。而且，我们将其用作工具 鉴定可以使靶向肿瘤细胞对免疫肿瘤疗法更敏感的药物。

项目成果

Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer.

• DOI: 10.1038/s41419-021-04029-4
• 发表时间: 2021-07-27
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Potter DS;Du R;Bhola P;Bueno R;Letai A
• 通讯作者: Letai A

Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer.

• DOI: 10.1186/s13058-020-01374-8
• 发表时间: 2020-11-30
• 期刊: Breast cancer research : BCR
• 作者: Zoeller JJ;Vagodny A;Daniels VW;Taneja K;Tan BY;DeRose YS;Fujita M;Welm AL;Letai A;Leverson JD;Blot V;Bronson RT;Dillon DA;Brugge JS
• 通讯作者: Brugge JS

Apoptosis: Directly Targeted at Last.

细胞凋亡：最终直接靶向。

• DOI: 10.1200/jco.22.00304
• 发表时间: 2022
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Letai,Anthony

Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma.

• DOI: 10.1038/s41467-023-38552-z
• 发表时间: 2023-05-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Potter, Danielle S. S.;Du, Ruochen;Bohl, Stephan R. R.;Chow, Kin-Hoe;Ligon, Keith L. L.;Bueno, Raphael;Letai, Anthony
• 通讯作者: Letai, Anthony