Defining genetic and metabolic requirements of aggressive breast cancer

定义侵袭性乳腺癌的遗传和代谢要求

• 批准号: 10611343
• 负责人: Susan E Waltz
• 金额: $ 46.65万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611343
• 关键词: Animal Model; Antineoplastic Agents; Automobile Driving; Biochemical Pathway; Biological Markers; Biological Process; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Treatment; Cancer Cell Growth; Cancer Prognosis; Carbon; Catabolic Process; Cell Compartmentation; Cell Culture Techniques; Cell physiology; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Chromatin; Clinical; Coupled; DEK gene; Data; Detection; Disease; Distal; Distant Metastasis; Drops; ERBB2 gene; Enzymes; Estrogen receptor positive; Gene Expression Profiling; Gene Expression Regulation; Genetic; Genus Hippocampus; Glycolysis; Goals; Growth; Human; Individual; Joints; Laboratories; Link; Mammary Neoplasms; Maps; Mediator; Metabolic; Metabolic Pathway; Metabolism; Metastatic breast cancer; Metastatic/Recurrent; Molecular; Mus; Neoplasm Metastasis; Nitrogen; Nuclear; Nutrient; Oncogenes; Outcome; Pathway interactions; Patients; Phenotype; Population; Prevention; Preventive measure; Preventive treatment; Process; Production; Prognosis; Property; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Recommendation; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Recurrent tumor; Reporting; Resistance; Resolution; Role; Sampling; Scientist; Signal Transduction; Source; Specimen; Testing; Therapeutic; Transcription Coactivator; Transcriptional Activation; Tumor Biology; United States; Up-Regulation; Woman; advanced breast cancer; aggressive breast cancer; beta catenin; breast cancer progression; cancer cell; cancer diagnosis; cancer recurrence; cancer stem cell; cancer subtypes; cancer survival; cancer therapy; candidate identification; candidate marker; cell growth; cell motility; chemotherapy; cholesterol biosynthesis; clinically relevant; hormone therapy; in vivo; insight; knowledge of results; macromolecule; malignant breast neoplasm; metabolomics; mortality; mouse model; neoplastic cell; novel; overexpression; pre-clinical; programs; response; risk prediction; self-renewal; side effect; sobriety; stable isotope; stem-like cell; tool; transcription factor; treatment strategy; tumor; tumor growth; tumor initiation; tumor metabolism; tumor progression

ABSTRACT While mortality rates for breast cancer (BC) have dropped precipitously over the past few decades due primarily to advances in treatment and detection, more than 42,000 individuals in the US will still die of this disease in 2019. These BC deaths are largely attributed to recurrent and metastatic disease. While classifiers such as ER positivity and HER2 status provide insights into BC prognosis and treatment, local and distal BC recurrence occurs across all BC subtypes. Due to our current inability to predict or prevent BC recurrence, BC is one of the most overtreated diseases with patients undergoing extended rounds of chemotherapy and treatment that may provide only marginal benefit. This is especially evident with ER+ (luminal) BCs where long term treatment with hormonal therapies is recommended for many patients, despite side effects, as a result of our inability to effectively predict the risk of late recurrence within this group. As such, there is a clear need to better understand the biology of BC recurrence and to devise a means to treat and/or prevent BC progression. Toward this goal, we have identified the RON receptor tyrosine kinase and the nuclear DEK oncogene as a signal transduction axis whose upregulation promotes BC growth and supports BC stem-like cell (BCSC) populations, which are considered a prime driver of recurrent and metastatic disease. Clinically, RON and DEK are frequently overexpressed in BC and their combined expression is highly predictive of BC recurrence, distant metastasis and death in patients across all human BC subtypes. We previously reported that high RON-DEK levels are strongly associated with β-catenin accumulation in human BC samples and that β-catenin is a synergistically activated target of RON and DEK. Recent discoveries in our laboratories show that RON or DEK overexpression increase the levels of key enzymes required for glycolysis, lactate production, and for cholesterol biosynthesis. We further show that RON and DEK expression increase glycolytic flux consistent with new studies highlighting metabolic shifts in response to β-catenin activation. Based on this data, we hypothesize that RON-DEK signaling acts, at least in part, through β-catenin to reprogram metabolic flux for sustaining the energy and macromolecule synthesis required for BC progression. Thus, the goal of this application is to determine the mechanistic roles of β-catenin and metabolic reprograming in RON/DEK-driven BC recurrence, and to define and therapeutically block metabolic effectors of this signaling axis to prevent BC progression and recurrence. Metabolic flux studies will be carried out in syngeneic animal models of BC and in live human BC specimens. These studies will be performed by a team of scientists and clinicians, and include a renowned expert in stable isotope resolved metabolomics approaches, that will be utilized to define RON/DEK dependent anabolic/catabolic processes. This untargeted approach is expected to identify candidate biomarkers and effectors of aggressive tumors with high RON/DEK expression. The supposition is that targeting vulnerable nodes of the RON/DEK metabolic signature will be an efficacious strategy for the treatment of advanced BC phenotypes.

摘要 虽然乳腺癌（BC）的死亡率在过去几十年中急剧下降， 由于治疗和检测的进步，美国仍将有42，000多人死于这种疾病， 2019.这些BC死亡主要归因于复发性和转移性疾病。而ER等分类器 阳性和HER 2状态提供了对BC预后和治疗、局部和远端BC复发的见解 发生在所有BC亚型中。由于我们目前无法预测或预防BC复发，BC是 大多数过度治疗的疾病，患者接受了长时间的化疗和治疗， 只提供边际效益。这对于ER+（管腔）BC尤其明显，其中长期用 激素疗法被推荐给许多患者，尽管有副作用，由于我们无法 有效预测该组中晚期复发的风险。因此，显然需要更好地了解 BC复发的生物学和设计治疗和/或预防BC进展的方法。为了实现这一目标， 我们已经鉴定了罗恩受体酪氨酸激酶和核DEK癌基因作为信号转导通路 轴，其上调促进BC生长并支持BC干细胞样细胞（BCSC）群体， 被认为是复发和转移性疾病的主要驱动因素。临床上，罗恩和DEK经常 在BC中过表达和它们的联合表达高度预测BC复发、远处转移 以及所有人类BC亚型患者的死亡率。我们以前报道过，高RON-DEK水平是 与β-连环蛋白在人BC样品中积累密切相关，β-连环蛋白是一种协同作用， 激活罗恩和DEK的靶点。我们实验室的最新发现表明，罗恩或DEK过表达 增加糖酵解、乳酸生产和胆固醇生物合成所需的关键酶的水平。 我们进一步表明，罗恩和DEK表达增加糖酵解通量与新的研究一致，强调 β-连环蛋白激活后的代谢变化。基于这些数据，我们假设RON-DEK信号传导 至少部分地通过β-连环蛋白来重编程代谢流，以维持能量和大分子 BC进展所需的合成。因此，本申请的目标是确定以下各项的机械作用： β-catenin和代谢重编程在罗恩/DEK驱动的BC复发中的作用，并定义和治疗 阻断该信号传导轴的代谢效应物以防止BC进展和复发。代谢通量研究 将在BC的同基因动物模型和活的人类BC标本中进行。这些研究报告将 由科学家和临床医生组成的团队进行，其中包括稳定同位素解析领域的知名专家 代谢组学方法，将用于定义罗恩/DEK依赖性合成代谢/分解代谢过程。这 预期非靶向方法可鉴定具有高侵袭性的侵袭性肿瘤的候选生物标志物和效应物。 罗恩/DEK表达。假设靶向罗恩/DEK代谢特征的脆弱节点 将是治疗晚期BC表型的有效策略。