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。

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.