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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

基本信息

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
项目类别：
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

项目摘要

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是分离将某些促死亡 BCL-2 家族 BH3-only 蛋白转化为基于促凋亡的“敏化剂”和“激活剂” 功能。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。促凋亡蛋白的 BH3 结构域。我设计了第一个小鼠模型，证明了 BCL-2 功能本身就足以使癌症缓解。接下来，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 在多种疾病中的作用。迄今为止，其中最成功的项目是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细胞凋亡。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化疗治疗成功的重要决定因素。此外，差异性细胞凋亡启动是常规化疗有治疗指数的主要原因——大多数非恶性躯体细胞与化学敏感的癌细胞相比，细胞的凋亡准备程度要低得多。基于这一发现，我们询问了我们是否可以找到能够选择性增强癌细胞凋亡启动的药物。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细胞凋亡启动的增加使用动态 BH3 分析 (DBP)。启动增加被测量为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。在过去的几年里，我们发现， 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，实体和液体肿瘤。与大多数其他离体药物敏感性策略相比，DBP 的一个重要优势是 DBP 离体培养时间不超过 24 小时。这克服了一般性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 作为许多液体和实体瘤的发现工具和预测生物标志物。此外，我们将其用作工具确定可以使靶肿瘤细胞对免疫肿瘤治疗更加敏感的药物。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

Navitoclax在表达EGFR的三阴性乳腺癌的PDX模型中增强了EGFR靶向的抗体 - 药物结合物的有效性。

DOI：
10.1186/s13058-020-01374-8
发表时间：
2020-11-30
期刊：
Breast cancer research : BCR
影响因子：
0
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

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

Apoptosis: Directly Targeted at Last.

细胞凋亡：最终直接靶向。