Diapause-like adaptation of triple-negative breast cancer cells during chemotherapy treatment

三阴性乳腺癌细胞在化疗期间的滞育样适应

• 批准号: 10616703
• 负责人: Eugen Dhimolea
• 金额: $ 19.13万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616703
• 关键词: 3-Dimensional; Adopted; Aftercare; Anabolism; Antineoplastic Agents; Apoptotic; Attenuated; Biological; Biological Assay; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Bromodomains and extra-terminal domain inhibitor; Cancer Model; Clinical; Clinical Management; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Dependence; Development; Diapause; Disease; Disease model; Disease remission; Drug Modelings; Embryo; Evaluation; Genes; Genetic Transcription; Genomics; Goals; Growth; Investigational Drugs; Lesion; Maintenance; Malignant Neoplasms; Maps; Mediating; Mediator; Methods; Minor; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Organoids; Outcome; Oxidation-Reduction; Paper; Pathologic; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Principal Investigator; Recurrent disease; Relapse; Research; Residual Cancers; Residual Neoplasm; Residual state; Role; Stress; System; Techniques; Therapeutic; Time; Validation; Writing; cancer cell; cancer subtypes; chemotherapy; clinically relevant; gain of function; high risk; in vitro Model; in vivo; loss of function; malignant breast neoplasm; neoplastic cell; personalized medicine; pharmacologic; pre-clinical; programs; relapse patients; relapse risk; response; simulation; therapeutic target; therapy development; triple-negative invasive breast carcinoma; tumor; tumor eradication; two-dimensional

PROJECT SUMMARY Treatment with cytotoxic drugs often fail to completely eradicate breast cancers (BrCa) due to viable tumor cells that persist (“residual tumors”) and represent a reservoir for eventual relapse. In triple-negative breast cancer (TNBC), a highly lethal BrCa subtype, the presence of post-treatment residual cancer cells is strongly associated with aggressive disease relapse. Eradicating the drug-persistent TNBC foci could lead to cures, but their therapeutic vulnerabilities remain elusive, mainly because bona fide preclinical models of this cancer cell state amenable to genomic and pharmacological interrogation had been lacking. In our recent studies we demonstrated that treatment-persistent residual tumor cells adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. Importantly, we developed 3-dimensional (3D) organoid based in vitro models (treatment-persistent organoids, TP-organoids) that faithfully recapitulate the phenotype and molecular profile of the residual tumors in PDX and in BrCa patients. To our knowledge, this is a first in vitro model of post-chemotherapy residual dormant cancer lesions. Our molecular and functional analyses strongly suggest that chemo-persistent dormant tumor cells possess distinct genomic and pharmacological vulnerabilities that are not reflected by historical cancer models (e.g. 2D cultures or conventional 3D/organoid cultures). The novelty and relevance of our models warrant the evaluation of putative mediators of the drug-persistent cancer cell state, which could reveal new, previously unappreciated, therapeutic targets for this clinically critical setting. In this exploratory project, we will combine our TNBC TP-organoid models of drug-persistent dormancy with genomic and pharmacological methods to i) identify the key mediators controlling TNBC cell exit from the dormancy state; and ii) develop therapeutic approaches that specifically kill dormant drug-persistent TNBC tumors. We will apply controllable loss-of-function (LOF) and gain-of-function (GOF) techniques to determine whether reactivation of Myc and/or other genes is necessary or sufficient for BrCa cells to exit dormancy. Similarly, we will use LOF approaches targeting genes commonly upregulated in our preclinical models of residual disease to assess their role on the viability of diapause-like persistent TNBC cells. In parallel, we will leverage the high-throughput capacity of our TP-organoid systems to map the landscape of pharmacological vulnerabilities of the chemo-persistent TNBC cells. The therapeutic value of candidate targets that enable the viability of persistent TNBC cells, or their exit from the dormant state, will be validated in appropriate in vivo residual disease models. This exploratory project will outline a first preclinical framework of therapeutic approaches to specifically target diapause-like drug-persistent TNBC tumors. Specifically targeting the candidate mediators that enable the viability during, or the exit from, treatment-induced protective dormancy of persistent residual cancer cells could lead to durable responses or even tumor eradication.

项目概要 由于肿瘤细胞存活，细胞毒性药物治疗通常无法完全根除乳腺癌 (BrCa) 持续存在的肿瘤（“残留肿瘤”）并代表最终复发的储存库。在三阴性乳腺癌中 (TNBC)，一种高度致命的 BrCa 亚型，治疗后残留癌细胞的存在密切相关 患有侵袭性疾病复发。根除药物持久性 TNBC 病灶可能会带来治愈，但它们 治疗的弱点仍然难以捉摸，主要是因为这种癌细胞状态的真实临床前模型 缺乏接受基因组和药理学审讯的能力。在我们最近的研究中，我们 证明持续治疗的残留肿瘤细胞采用独特且可逆的转录 类似于胚胎滞育的程序，这是由压力引发的暂停发育的休眠阶段 并与 Myc 活性和整体生物合成受到抑制有关。重要的是，我们开发了 3 维 (3D) 基于类器官的体外模型（治疗持续性类器官，TP-类器官），忠实地再现 PDX 和 BrCa 患者中残留肿瘤的表型和分子特征。据我们所知，这 是第一个化疗后残留休眠癌症病灶的体外模型。我们的分子和功能 分析强烈表明，化疗持续休眠的肿瘤细胞具有独特的基因组和 历史癌症模型（例如 2D 培养物或 传统 3D/类器官培养）。我们模型的新颖性和相关性保证了对假定的评估 药物持续性癌细胞状态的介质，可能揭示新的、以前未被重视的治疗方法 这种临床关键环境的目标。在这个探索性项目中，我们将结合我们的 TNBC TP 类器官模型 使用基因组和药理学方法来研究药物持续休眠，以 i) 确定关键介质 控制TNBC细胞退出休眠状态； ii) 开发专门杀死病毒的治疗方法 休眠药物持续性 TNBC 肿瘤。我们将应用可控功能丧失（LOF）和功能获得 (GOF) 技术来确定 Myc 和/或其他基因的重新激活是否是必要或充分的 BrCa 细胞退出休眠。同样，我们将使用 LOF 方法来靶向通常上调的基因 我们的残留病临床前模型评估其对滞育样持续性 TNBC 生存能力的作用 细胞。与此同时，我们将利用 TP 类器官系统的高通量能力来绘制景观图 化疗持续性 TNBC 细胞的药理学脆弱性。候选靶点的治疗价值 使持久性 TNBC 细胞的生存能力或它们退出休眠状态的技术将在 适当的体内残留疾病模型。该探索性项目将概述第一个临床前框架 专门针对滞育样药物持续性 TNBC 肿瘤的治疗方法。针对性明确 候选介体能够在治疗引起的保护性休眠期间保持活力或从中退出 持续残留的癌细胞可能会导致持久的反应甚至肿瘤根除。