Normalizing Breast Cancer Metabolism to Prevent Progression and Recurrence (PQ21)

描述（由申请人提供）：乳腺癌是女性中最常见的癌症，经常扩散和复发，因此导致高死亡率。尽管手术和治疗取得了进展，但标准护理仍然主要依赖于旨在杀死肿瘤细胞的化疗和放疗。进化模型预测，这些方法施加的选择压力导致抗性克隆的生存，最终重新激活疾病。基于癌症中代谢性肿瘤细胞改变的中心参与，本申请遵循 假设肿瘤细胞代谢的治疗正常化可以阻止乳腺癌进展并防止复发。如果成功，这种方法不会根除所有残留疾病，而是实现和保持无疾病状态。原则上，旨在使肿瘤细胞代谢正常化的治疗不会施加选择压力，因此不利于逃逸克隆的渗透以驱动复发。如果成功，治疗性代谢重编程可能成为乳腺癌护理的关键组成部分，并通过降低乳腺癌死亡率对整体结果产生革命性影响。在确定了异常肿瘤细胞线粒体复合物I功能、致癌生长和乳腺癌转移进展之间的因果关系后，这一信息转化为一种新的策略，其中NAD+/通过用NAD前体处理的NADH氧化还原平衡导致异种移植模型中肿瘤生长和转移性疾病的抑制，以及癌基因驱动的转基因乳腺癌中乳腺癌进展的干扰。自发性乳腺癌模型。基于这些发现，拟议的研究旨在1.评估NAD前体治疗在乳腺癌进展的异种移植和转基因小鼠模型中的功效，包括与标准护理的组合; 2.采用靶向代谢组学，使用ESI QQQ和NIMS技术，结合XCMS代谢组学生物信息学，在疾病进展和治疗的定义阶段中定义肿瘤细胞NAD+/NADH代谢组;以及3.生成乳腺癌进展阶段的非靶向综合代谢谱。我们的研究结果可能会确定肿瘤细胞代谢的治疗正常化，例如通过NAD前体治疗，作为一种有效的，无毒的方式来沉默乳腺癌和预防复发。乳腺癌进展的代谢组学将赋予该领域权力，并使基于代谢正常化概念的预防方法得以发展。利用所产生的信息进行互动和协作，将有助于降低乳腺癌患者的死亡率。 公共卫生相关性：该项目解决了NCI的挑衅性问题PQ 21：“鉴于对细胞杀伤疗法的抗性，我们能否通过使用保持肿瘤静止的方法来延长生存期？“尽管乳腺癌手术和治疗有所改善，但乳腺癌患者的死亡率基本保持不变。一个主要的潜在问题是，这种疾病经常复发，通常是在最初的辅助治疗明显成功多年后。目前，护理标准主要依赖于旨在根除快速分裂的肿瘤细胞的化疗和放疗。然而，这些治疗很可能会选择更具侵略性的肿瘤细胞，最终重新激活疾病，并对治疗产生抗药性。具有干细胞样特征的休眠或缓慢分裂的肿瘤细胞也可能不受影响并导致复发。我们假设乳腺癌细胞，无论最初的转化事件和疾病驱动机制如何，都依赖于改变的代谢回路，这使得肿瘤细胞不仅能够满足其加速生长的能量需求，而且还能够在肿瘤微环境的生态位内改变对营养物质和氧气的获取条件下生存。基于我们的研究结果和代谢肿瘤细胞改变在疾病进展中的中心参与，我们预测肿瘤细胞代谢的治疗正常化可以阻止乳腺癌进展并预防复发。如果成功的话，这种方法不会根除所有的残留疾病，而是实现和保持无临床疾病的状态。原则上，旨在使肿瘤细胞代谢正常化的治疗不会施加选择性压力，因此不会有利于逃逸克隆或癌症干细胞的渗透，从而可能导致复发。因此，治疗性代谢重编程可能成为乳腺癌治疗的关键组成部分，并通过降低乳腺癌死亡率对整体结局产生革命性影响。

DESCRIPTION (provided by applicant): Breast cancer is the most prevalent cancer in women that frequently spreads and recurs, thus leading to high mortality. Despite advances in surgery and treatment, standard of care still relies primarily on chemo- and radiation therapies aimed at killing the tumor cells. Evolutionary models predict that selective pressure imposed by these approaches causes survival of resistant clones that eventually re-activate the disease. Based on the central involvement of metabolic tumor cell alterations in cancer, this application follows the hypothesis that therapeutic normalization of tumor cell metabolism can halt breast cancer progression and prevent relapse. If successful, this approach would not eradicate all residual disease, but rather achieve and maintain a disease symptom-free state. In principle, treatment aimed at normalizing tumor cell metabolism would not impose selective pressure, and thus not favor penetration of escaping clones to drive recurrence. If successful, therapeutic metabolic reprogramming could become a critical component of breast cancer care and have revolutionary impact on overall outcome by reducing the mortality in breast cancer. Having identified a cause-and-effect relationship between aberrant tumor cell mitochondrial complex I function, oncogenic growth, and metastatic progression in breast cancer, this information translated into a new strategy, where normalization of the NAD+/NADH redox balance through treatment with NAD precursors led to inhibition of tumor growth and metastatic disease in xenograft models and interference with breast cancer progression in an oncogene driven transgenic model of spontaneous breast cancer. Based on these findings, the proposed study seeks to 1. Evaluate the efficacy of NAD precursor treatment in xenograft and transgenic mouse models of breast cancer progression, including combination with standard of care; 2. Employ targeted metabolomics to define the tumor cell NAD+/NADH metabolome in defined stages of disease advancement and treatment using ESI QQQ and NIMS technology, combined with XCMS metabolomic bioinformatics; and 3. Generate untargeted comprehensive metabolic profiles of progressive stages in breast cancer. The outcome from our study may identify therapeutic normalization of tumor cell metabolism, e.g. through NAD precursor treatment, as an effective, non-toxic way to silence breast cancer and prevent recurrence. The metabolome of breast cancer progression will empower the field and enable development of preventive approaches based on the concept of metabolic normalization. Interactive and collaborative efforts using the information generated will help to reduce the mortality in breast cancer patients. PUBLIC HEALTH RELEVANCE: This project addresses NCIs provocative question PQ21: "Given the appearance of resistance in response to cell killing therapies, can we extend survival by using approaches that keep tumors static?" Despite improvements in breast cancer surgery and treatment, the mortality of breast cancer patients has largely remained unchanged. A major underlying problem is that the disease frequently recurs, often years after initial adjuvant therapy was apparently successful. At present, the standard of care relies primarily on chemo- and radiation therapies aimed at eradicating rapidly dividing tumor cells. However these treatments are very likely to select more aggressive tumor cells that eventually re-activate the disease and are treatment resistant. Dormant or slowly dividing tumor cells with stem-like characteristics could also remain unaffected and lead to recurrence. We hypothesize that breast cancer cells, regardless of the initial transforming event and disease driving mechanism, rely on altered metabolic circuitry that allows the tumor cells to meet their energy needs not only for accelerated growth, but also for survival under changing access to nutrients and oxygen within niches of the tumor microenvironment. Based on our result and the central involvement of metabolic tumor cell alterations in disease progression, we predict that therapeutic normalization of the tumor cell metabolism can halt breast cancer progression and prevent relapse. If successful, this approach would not eradicate all residual disease, but rather achieve and maintain a clinical disease symptom-free state. In principle, treatment aimed at normalizing tumor cell metabolism would not impose selective pressure and thus not favor penetration of escaping clones or cancer stem cells that could drive recurrence. Therefore, therapeutic metabolic reprogramming could become a critical component of breast cancer care and have revolutionary impact on overall outcome by reducing the mortality in breast cancer.