权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism of estrogen independent proliferation in ER+ breast cancer cells

ER乳腺癌细胞雌激素非依赖性增殖机制

基本信息

批准号：
10304408
负责人：
ANDREA Hope BILD
金额：
$ 59.62万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10304408
关键词：
Automobile Driving Biological Models Biopsy Breast Cancer Cell Breast Cancer Patient Bypass CDK4 gene Cancer Control Cancer Patient Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Line Cell Lineage Cell Proliferation Cell division Cells Cessation of life Chemosensitization Clinical Clinical Trials Collection Combined Modality Therapy Couples Cyclin-Dependent Kinase Inhibitor Data Dose Drug Combinations Drug Modelings Drug usage ERBB2 gene Effectiveness Endocrine Equilibrium Estrogen receptor positive Estrogens Evolution Feedback Gene Expression Gene Expression Profile Hand In Vitro Letrozole MAP Kinase Gene Maps Measurement Measures Mediating Mitogen-Activated Protein Kinase Kinases Modeling Outcome Study Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Population Preoperative Endocrine Therapy Repression Resistance Role Sampling Series Signal Pathway Signal Transduction System Testing Therapeutic Time Transitional Cell Neoplasm Tumor stage Up-Regulation base cancer cell cell type design drug testing experimental study hormone therapy improved outcome in vitro Model in vivo inhibitor/antagonist kinase inhibitor malignant breast neoplasm mathematical model neoplastic cell patient response personalized medicine prevent promoter reconstruction refractory cancer resistance mechanism response single-cell RNA sequencing targeted treatment therapy resistant tool transcriptomics treatment strategy tumor tumor heterogeneity

项目摘要

Abstract Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is variable. Our preliminary results examined the evolutionary trajectories of early stage breast cancer tumors using single cell transcriptomic profiling of serial tumor biopsies from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle inhibitor ribociclib. Resistant tumors with accelerated loss of estrogen signaling show up-regulation of the JNK pathway, while those that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that tumors cells can reactivate during combination treatment, indicating stronger selection for a proliferative state. We hypothesize that resistance to CDK4/6 inhibition in earlier stage breast cancer is driven by JNK MAPK pathway stimulation and reactivation of the cell cycle through promotion of CDK6 expression or decreased cell cycle inhibitor function. In Aim 1, we will use a new mechanistic model of CDK4/6 regulation by cell cycle Inhibitors and Promoters (CIP) that couples estrogen and JNK signaling with cell cycle progression to measure the mechanisms driving cell cycle activation in a series of isogenic cell lines sensitive and resistant to CDK4/6 and endocrine inhibitors and in patient tumor cells. This analysis will reveal how distinct signaling pathways contribute to cell cycle reactivation during estrogen, CDK4/6 and JNK inhibition treatments and provide signatures of each resistant mechanism across cell types, over time and between systems. Aim 2 leverages our collection of patient tumors from the FELINE clinical trial to discover the intracellular and intratumoral resistance mechanisms driving proliferation. Fundamental resistance mechanisms will be measured in over ~300,000 patient cells from 360 tumor samples using single cell RNA sequencing data already in hand to identify core intracellular signaling states that act alone or in concert to drive proliferation. Next, the population of cells within each tumor will be analyzed to quantify intratumoral heterogeneity and how resistant populations differ in growing or shrinking tumors during drug treatment. Applying CIP to project proliferation across patient tumor cells will allow prediction of inhibitor strategies that most effectively block intracellular and intratumoral proliferation. Lastly, Aim 3 will apply a series of JNK pathway drugs with clinical potential to design and test treatment strategies that maintain durable inhibition of proliferation in ER+ cancer cells. Iterative feedback between mathematical models and patient/experimental data serves to provide a deep understanding of cell cycle regulation and mechanisms of dysregulation leading to resistance. Together, these experiments will reveal the balance between estrogen and alternative mediated JNK signaling, and their roles in resistance and provide a guide for therapeutic regimes with more durable control of cancer cell proliferation.

抽象的细胞周期蛋白依赖性激酶 (CDK) 抑制剂与内分泌治疗相结合可改善转移性癌症的预后雌激素受体阳性 (ER+)、HER2 阴性、乳腺癌患者。但这个组合的价值在可能治愈的早期患者中，情况是可变的。我们的初步结果检验了进化使用连续肿瘤活检的单细胞转录组分析来确定早期乳腺癌肿瘤的轨迹来自单独术前内分泌治疗（来曲唑）或与细胞周期联合治疗的临床试验抑制剂 ribociclib。雌激素信号加速丧失的耐药肿瘤显示 JNK 上调途径，而那些在治疗期间维持雌激素信号传导的药物则显示出 CDK4/6 激活的增强与 ERBB4 和 ERK 信号上调一致。细胞周期重建发现肿瘤细胞可以在联合治疗期间重新激活，表明对增殖状态有更强的选择。我们假设早期乳腺癌对 CDK4/6 抑制的抵抗是由 JNK MAPK 驱动的通过促进 CDK6 表达来刺激和重新激活细胞周期或细胞周期抑制剂功能下降。在目标 1 中，我们将使用 CDK4/6 调节的新机制模型通过细胞周期抑制剂和启动子 (CIP) 将雌激素和 JNK 信号传导与细胞周期进程结合起来测量一系列敏感和耐药的同基因细胞系中驱动细胞周期激活的机制 CDK4/6 和内分泌抑制剂以及患者肿瘤细胞。该分析将揭示不同的信号传导如何途径有助于在雌激素、CDK4/6 和 JNK 抑制治疗期间重新激活细胞周期，并提供跨细胞类型、随时间变化和系统之间每种耐药机制的特征。目标 2 利用我们的从 FELINE 临床试验中收集患者肿瘤，以发现细胞内和肿瘤内耐药性驱动扩散的机制。基本阻力机制将在超过 300,000 个中进行测量使用现有的单细胞 RNA 测序数据从 360 个肿瘤样本中提取患者细胞来识别核心细胞内信号传导状态单独或协同作用以驱动增殖。接下来，内的细胞群将分析每个肿瘤以量化肿瘤内异质性以及耐药群体在生长方面的差异或在药物治疗期间缩小肿瘤。应用 CIP 来预测患者肿瘤细胞的增殖将允许预测最有效地阻止细胞内和肿瘤内增殖的抑制剂策略。最后， Aim 3将应用一系列具有临床潜力的JNK通路药物来设计和测试治疗策略，维持对 ER+ 癌细胞增殖的持久抑制。数学模型之间的迭代反馈患者/实验数据有助于深入了解细胞周期调节和机制失调导致抵抗。这些实验将共同揭示雌激素之间的平衡和替代介导的 JNK 信号传导，及其在耐药性中的作用，并为治疗方案提供指导更持久地控制癌细胞增殖。