Understanding metabolic and vascular vulnerabilities of residual disease in triple negative breast cancer to inform on treatment strategies

项目总结/摘要 逃避治疗的癌细胞复发是死亡的主要原因。考虑到残留疾病可以 在治疗后持续数年至数十年，它提供了第二个治疗窗口， 可以利用残留细胞来识别新的、可操作的靶点，从而减少或延迟复发。 不幸的是，残留疾病生存的机制仍然研究不足，部分原因是缺乏工具， 模型来精确研究残留疾病的进化性质。为此，代谢和血管 已经观察到重编程与治疗抵抗平行发生，并且先于解剖学变化 治疗后，因此有希望作为靶点，以改善临床结果。这项建议 将开发新的功能成像工具，以了解残留肿瘤的动态行为（F99期） 以及如何在残留疾病期间针对代谢和血管脆弱性以减轻复发 (K00阶段）。残留病灶的出现反映了肿瘤的时空异质性 微环境和癌细胞的进化特性，以适应治疗诱导的选择性压力。 因此，为了有效地监测治疗反应，需要一种系统级的图像代谢方法， 在能够可视化肿瘤内的空间分辨率下的肿瘤微环境的相关脉管系统 体内异质性是必要的，但目前还没有。在本提案的F99阶段，我的目标是设计 跟踪代谢和血管变化以识别代谢不同的新光学成像方法 化疗后出现的残留肿瘤亚群。在aim 1.1（以前的工作）中，我表明， 纵向评估肿瘤代谢和肿瘤内异质性， 在疾病消退、残留疾病和复发期间捕获诱导的代谢变化。目标1.2 （建议的工作），我将开发图像分割方法来量化1）细胞水平的代谢特征 和2）导致灌注不良的血管特性。我会检查是否对治疗的抵抗 代谢上不同的残留肿瘤亚群的特殊小生境的出现， 针对性地虽然功能成像方法由于其反映细胞和组织的能力而被期望， 水平的动力学，他们是不足以阐明所有的分子机制，驱动复发。在K 00 在这个建议的第一阶段，我将采取分子方法来深入研究PDX中残留疾病的机制 三阴性乳腺癌（TNBC）我将专注于靶向MYC致癌信号通路 为TNBC肿瘤的一个子集确定新的、可操作的代谢和血管残留疾病靶点。在 除了满足TNBC残留疾病治疗的迫切需求外，该培训计划还将提供 在成像和癌症生物学领域的领导者的特殊培训，定位我成为一个 在这两个领域的界面上完成了独立研究。

PROJECT SUMMARY/ABSTRACT Recurrence of cancer cells that evade therapy is a leading cause of death. Given that residual disease can persist for years to decades following therapy, it presents a second therapeutic window where the vulnerabilities of residual cells can be exploited to identify novel, actionable targets, thus reducing or delaying recurrence. Unfortunately, mechanisms of residual disease survival remain under-studied, partly due to the lack of tools and models to precisely study the evolutionary nature of residual disease. To this end, metabolic and vascular reprogramming have been observed to occur in parallel to therapy resistance and precede anatomical changes after treatment, and thus hold promise as targets to be leveraged to improve clinical outcomes. This proposal will develop novel functional imaging tools to understand the dynamic behaviors of residual tumors (F99 phase) and how metabolic and vascular vulnerabilities can be targeted during residual disease to mitigate recurrence (K00 phase). The emergence of residual disease reflects the spatiotemporal heterogeneities of the tumor microenvironment and the evolutionary property of cancer cells to adapt to therapy-induced selective pressures. Therefore, to effectively monitor treatment responses, a systems-level approach to image metabolism and the associated vasculature of the tumor microenvironment at a spatial resolution capable of visualizing intra-tumoral heterogeneity in vivo is necessary, but currently unavailable. In the F99 phase of this proposal, I aim to design novel optical imaging methodologies to track metabolic and vascular shifts to identify metabolically distinct residual tumor subpopulations that emerge following chemotherapy. In aim 1.1 (previous work), I show that longitudinal assessment of bulk tumor metabolism and intra-tumoral heterogeneity enables chemotherapy induced metabolic shifts to be captured during disease regression, residual disease, and recurrence. In aim 1.2 (proposed work), I will develop image segmentation approaches to quantify 1) cellular-level metabolic features and 2) vascular characteristics that lead to poor perfusion. I will examine whether resistance to treatment leads to the emergence of specialized niches of metabolically distinct residual tumor subpopulations that could be targeted. While functional imaging approaches are desirable due to their ability to reflect cellular, and tissue- level dynamics, they are insufficient to elucidate all the molecular mechanisms that drive recurrence. In the K00 phase of this proposal, I will take a molecular approach to delve into the mechanisms of residual disease in PDX models of Triple Negative Breast Cancer (TNBC). I will focus on targeting MYC oncogenic signaling pathways to identify novel, actionable metabolic and vascular targets of residual disease for a subset of TNBC tumors. In addition to filling a critical need for the treatment of residual disease in TNBC, this training plan will provide exceptional training by leaders in the imaging and cancer biology fields, positioning me to become an accomplished independent researcher at the interface of these two fields.