Collaborative Research in Integrative Cancer Biology

综合癌症生物学合作研究

基本信息

批准号：
8928084
负责人：
Robert R. Clarke
金额：
$ 56.44万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928084
关键词：
Address Adenocarcinoma Adjuvant Animal Model Apoptosis Automobile Driving Autophagocytosis Benchmarking Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Cancer Biology Cell Proliferation Cells Cessation of life Classification Complementary DNA Computer Simulation Consensus Cytotoxic Chemotherapy DNA Modification Methylases Data Data Set Diagnosis Distant Distant Metastasis ERR1 protein ESR1 gene Endocrine Environment Epigenetic Process Equilibrium Estrogen Receptor alpha Event Exhibits Exposure to Gene Expression Profile Genes Goals Growth Health Histone Deacetylase Housing Human Immune Incidence Individual Informatics Interdisciplinary Study Intervention Machine Learning Maintenance Malignant Neoplasms Mammary Neoplasms Markov chain Monte Carlo methodology Messenger RNA Metabolic Metabolism Modeling Molecular Neoplasm Metastasis Newly Diagnosed Patient risk Patients Pharmaceutical Preparations Phenotype Population Sizes Primary Neoplasm Proliferating Property Proteins RNA Interference Rattus Recurrence Recurrent tumor Research Residual Tumors Risk Rodent Model Sampling Signal Transduction Source Specimen Systemic Therapy Tamoxifen Technology Testing Time Training Validation Walking Woman Work breast cancer diagnosis design dimethylbenzanthracene experience high risk hormone therapy human data inhibitor/antagonist innovation insight malignant breast neoplasm meetings multidisciplinary network models novel novel therapeutic intervention novel therapeutics overexpression paracrine programs response tool treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Breast tumors expressing estrogen receptor-alpha (ER) tend to be less responsive to cytotoxic chemotherapy than ER-negative breast cancers; advanced ER+ breast cancer remains largely incurable. Moreover, this breast cancer subtype frequently exhibits marked dormancy, conferring upon patients a high risk of experiencing a late recurrence (emergence from dormancy) that persists for decades after their initial diagnosis and treatment. Why ER+ breast is the most strongly associated with dormancy is unknown and represents a critical barrier to progress in the field. Since 70% of newly diagnosed breast cancers are ER+ but ~50% of these eventually recur, many doing so years after cessation of an otherwise apparently successful initial intervention, significance of the dormant phenotype is clear. Using transcriptome data from pretreatment tumors from women with ER+ breast cancer who were subsequently treated with tamoxifen (TAM) as their only systemic therapy, we derived an initial molecular classifier that robustly separates early (d 3 yrs) from late (e 5 yrs; emergence from dormancy) distant recurrences in both training and independent datasets. We then identified novel features of the "early" (E) vs. "late" (L) signaling network's topology in thse datasets. We also developed an adaptation of the DMBA-induced rat mammary tumor model and show that it represents E, L, and "not" (N) recurring tumors, molecular features of which are present in human breast tumors and cell lines. Mechanistically, our data implicate a "rewiring" (including epigenetic events) of the signaling from the unfolded protein response (UPR) and autophagy, and adaptations in cellular metabolism, as the molecular events that may enable cells to maintain, and later escape from, dormancy. Our central hypothesis is that dormancy reflects the growth arrest induced by endocrine therapies in both residual tumors (in-breast recurrences) and micro-metastases (distant recurrences), and that the signaling maintaining dormancy after systemic therapy ends is epigenetically regulated. Indeed, prolonged hormone therapy may well work by extending dormancy. Individual cells can emerge from dormancy as their metabolic capacity becomes sufficient to support both survival and replication, and the integrated balance between autophagy (prosurvival) and apoptosis (prodeath) signaling enables more cells in a tumor to proliferate and the tumor population size to grow. We propose an integrated, multidisciplinary research program that, if successful, will generate innovative insights into the molecular drivers of dormancy in ER+ breast cancers, develop new in silico signaling models, identify predictors of patient risk to experience a late recurrence, and explore mechanisms of dormancy with the longer term goal of discovering potentially novel therapeutic interventions.

描述（由申请人提供）：表达雌激素受体-α（ER）的乳腺肿瘤往往比 ER 阴性乳腺癌对细胞毒性化疗的反应更差；晚期 ER+ 乳腺癌在很大程度上仍然无法治愈。此外，这种乳腺癌亚型经常表现出明显的休眠状态，使患者在初次诊断和治疗后持续数十年的晚期复发（从休眠状态中恢复）的风险很高。为什么 ER+ 乳房与休眠最密切相关尚不清楚，并且是该领域进展的关键障碍。由于新诊断的乳腺癌中有 70% 是 ER+，但其中约 50% 最终会复发，其中许多人是在停止原本看似成功的初始干预多年后才复发，因此休眠表型的重要性是显而易见的。使用来自 ER+ 乳腺癌女性的治疗前肿瘤的转录组数据，这些女性随后接受了他莫昔芬 (TAM) 作为唯一的全身治疗，我们得出了一个初始分子分类器，该分类器可以有力地区分早期（d 3 年）和晚期（e 5 年；出现）从休眠状态）在训练和独立数据集中的远距离复发。然后，我们在这些数据集中确定了“早期”(E) 与“晚期”(L) 信号网络拓扑的新特征。我们还开发了 DMBA 诱导的大鼠乳腺肿瘤模型的改编版，并表明它代表 E、L 和“非”(N) 复发肿瘤，其分子特征存在于人类乳腺肿瘤和细胞系中。从机制上讲，我们的数据暗示了来自未折叠蛋白反应（UPR）和自噬的信号的“重新布线”（包括表观遗传事件），以及细胞代谢的适应，因为分子事件可能使细胞能够维持并随后逃脱，休眠。我们的中心假设是，休眠反映了内分泌治疗在残留肿瘤（乳腺内复发）和微转移（远处复发）中引起的生长停滞，并且系统治疗结束后维持休眠的信号是表观遗传调节的。事实上，长期激素治疗可能通过延长休眠期而发挥作用。当单个细胞的代谢能力足以支持生存和复制时，它们就可以从休眠状态中苏醒，并且自噬（促生存）和细胞凋亡（促死亡）信号之间的综合平衡使肿瘤中更多的细胞能够增殖，肿瘤群体规模得以增长。我们提出了一个综合的、多学科的研究计划，如果成功，将产生对 ER+ 乳腺癌休眠的分子驱动因素的创新见解，开发新的计算机信号传导模型，确定患者晚期复发风险的预测因子，并探索晚期复发的机制。休眠的长期目标是发现潜在的新型治疗干预措施。