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）的乳腺肿瘤对细胞毒性化学疗法的反应较小，而不是ER阴性的乳腺癌；晚期ER+乳腺癌基本无法治愈。此外，这种乳腺癌亚型经常表现出明显的休眠状态，并赋予患者的高风险患有晚期复发（从休眠中出现），这些风险在最初的诊断和治疗后数十年持续了数十年。为什么ER+乳房与休眠最密切相关，这是未知的，这代表了该领域进步的关键障碍。由于有70％的新诊断的乳腺癌是ER+，但其中约有50％最终复发，许多人在停止原本成功的初始干预后几年，休眠表型的重要性很明显。我们使用来自ER+乳腺癌女性的经过预处理肿瘤的转录组数据，后来用他莫昔芬（TAM）治疗作为其唯一的全身疗法，我们得出了一种初始分子分类剂，该分子分类剂在较晚（E 5 yrs; e 5 yrs; eft yrs;从休眠和独立的培训）中进行了良好的分子分类（d 3年）。然后，我们确定了“早期”（E）与“晚期”（L）信号网络在THSE数据集中的拓扑结构的新功能。我们还开发了DMBA诱导的大鼠乳腺肿瘤模型的适应性，并表明它代表E，L和“不是”（N）重复发生的肿瘤，其分子特征存在于人类乳腺肿瘤和细胞系中。从机械上讲，我们的数据暗示了来自未折叠的蛋白质反应（UPR）和自噬的信号传导的“重新启动”（包括表观遗传事件），以及细胞代谢的适应性，作为可能使细胞能够维持并随后逃避休眠的分子事件。我们的中心假设是，休眠反映了残留肿瘤（内外复发）和微构酶（远处复发）中内分泌疗法引起的生长停滞，并且在全身治疗末端保持休眠的信号传导均表现出表观调节。实际上，长时间的激素治疗可能通过延伸休眠来很好地发挥作用。由于其代谢能力足以支持生存和复制，并且自噬（Prosurvival）和凋亡（Prodeath）信号在肿瘤中增加了更多细胞，可以增殖，并且肿瘤种群大小。我们提出了一项综合的多学科研究计划，如果成功，它将对ER+乳腺癌中休眠的分子驱动因素产生创新的见解，在硅信号信号模型中开发新的，确定患者风险的预测因素，可以经历晚期复发的预测指标，并探索潜在的新型新颖的临时互动率，并探索了处于较长期限的潜在机制。