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.

项目摘要 细胞毒性药物的治疗通常由于肿瘤细胞而无法完全放射性乳腺癌（BRCA） 持续存在（“残留肿瘤”），代表了最终缓解的水库。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 侵略性疾病缓解。根除毒品抗药性的TNBC焦点可以导致治疗方法，但它们的治疗方法 治疗脆弱性仍然难以捉摸，主要是因为该癌细胞状态的真正临床前模型 缺乏对基因组和药物询问的不适。在我们最近的研究中 证明治疗性残留肿瘤细胞采用独特而可逆的转录 计划重新组合胚胎滞育，这是由压力触发的悬浮发育的休眠阶段 并与抑制MYC活性和整体生物合成有关。重要的是，我们开发了三维 （3D）基于类器官的体外模型（治疗 - 持久性器官，TP - 细胞机构），忠实地概括 PDX和BRCA患者残留肿瘤的表型和分子谱。据我们所知，这个 是治疗后残留休眠癌病变的第一个体外模型。我们的分子和功能 分析强烈表明，化学性休眠性肿瘤细胞具有不同的基因组和 没有历史癌症模型反映的药理脆弱性（例如2D培养或 常规的3D/器官培养物）。我们的模型的新颖性和相关性值得评估推定 药物抗药性癌细胞状态的介质，该状态可能揭示新的，以前未接受的治疗 该临床关键环境的目标。在这个探索性项目中，我们将结合TNBC TP-Organoid模型 与基因组和药物方法的毒品抗性休眠，i）确定关键介体 控制TNBC细胞从休眠状态退出； ii）开发专门杀死的治疗方法 休眠的药物抗药性TNBC肿瘤。我们将应用控制器功能丧失（LOF）和功能奖励 （GOF）确定MYC和/或其他基因重新激活是否需要或足够的技术 BRCA细胞退出休眠。同样，我们将使用针对通常更新基因的LOF方法 我们的残留疾病的临床前模型，以评估其在类似糖尿病的持续性TNBC的生存能力中的作用 细胞。同时，我们将利用TP-核系统的高通量容量来绘制景观 化学抗性TNBC细胞的药物脆弱性。候选目标的治疗价值 这使得持续的TNBC单元或它们从休眠状态退出的可行性将在 合适的体内残留疾病模型。这个探索性项目将概述一个第一个临床前框架 特异性靶向类似糖尿病的药物抗药性TNBC肿瘤的治疗方法。专门定位 在治疗诱导的受保护休眠期间或退出期间或退出期间可生存的候选者 持续的残留癌细胞可能会导致持久反应甚至肿瘤放射。