Defining genetic and metabolic requirements of aggressive breast cancer

摘要 虽然乳腺癌(BC)的死亡率在过去几十年里急剧下降，主要原因是 随着治疗和检测的进步，#年美国仍有超过4.2万人死于这种疾病 2019年。这些BC死亡在很大程度上归因于复发和转移性疾病。而ER等量词 阳性和HER2状态有助于了解结直肠癌的预后和治疗、局部和远端结直肠癌复发 在所有BC子类型中发生。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，患者接受长时间的化疗和治疗，可能 只提供边际利益。这一点在ER+(腔)BCS中尤其明显，长期使用 激素疗法被推荐给许多患者，尽管有副作用，因为我们无法 有效地预测该组内晚期复发的风险。因此，显然有必要更好地理解 研究BC复发的生物学，并设计一种治疗和/或防止BC进展的方法。为了实现这个目标， 我们已经确定RON受体酪氨酸激酶和核DEK癌基因是一种信号转导 其上调促进BC生长并支持BC干细胞(BCSC)群体的轴，这是 被认为是复发和转移性疾病的主要驱动力。临床上，罗恩和德克经常 BC过表达及其联合表达对BC复发、远处转移有高度预测意义 以及所有人类BC亚型患者的死亡。我们之前报告过，高Ron-dek水平是 与人BC样本中β-连环蛋白蓄积密切相关，β-连环蛋白是协同作用的 罗恩和德克的目标被激活。我们实验室的最新发现表明，RON或DEK过度表达 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，RON和DEK的表达增加了糖酵解通量，这与新的研究强调的一致 响应β-连环蛋白激活的代谢变化。基于这些数据，我们假设Ron-dek信号 至少部分地通过β-连环蛋白来重新编程代谢流，以维持能量和大分子 BC级进所需的合成。因此，此应用程序的目标是确定 β-连环蛋白和代谢重编程在RON/DEK驱动的BC复发中的作用，并定义和治疗 阻断该信号轴的代谢效应，以防止BC进展和复发。代谢流研究 将在同基因的BC动物模型和活体人类BC标本中进行。这些研究将是 由一组科学家和临床医生执行，其中包括一位稳定同位素解析的著名专家 代谢组学方法，将被用来定义依赖RON/DEK的合成代谢/分解代谢过程。这 非靶向方法有望识别高侵袭性肿瘤的候选生物标志物和效应物 RON/DEK表达式。假设以RON/DEK代谢特征易受攻击节点为靶点 将是治疗晚期BC表型的有效策略。

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.