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

描述(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。尽管在手术和治疗方面取得了进展，但标准的护理仍然主要依赖于旨在杀死肿瘤细胞的化疗和放射治疗。进化模型预测，这些方法施加的选择性压力会导致抗性克隆存活，最终重新激活疾病。基于代谢性肿瘤细胞改变在癌症中的中心参与，这一应用遵循 假设肿瘤细胞代谢的治疗正常化可以阻止乳腺癌的进展和防止复发。如果成功，这种方法将不会根除所有残留疾病，而是实现并保持无疾病症状状态。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，因此不利于通过穿透逃逸的克隆来推动复发。如果成功，治疗性代谢重新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总体结果产生革命性影响。在确定了异常的肿瘤细胞线粒体复合体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，通过NAD前体治疗使NAD/NADH氧化还原平衡正常化，在异种移植模型中抑制肿瘤生长和转移疾病，并在癌基因驱动的自发性乳腺癌转基因模型中干扰乳腺癌进展。基于这些发现，这项拟议的研究试图1.评估NAD前体在异种移植和乳腺癌进展转基因小鼠模型中的疗效，包括与标准护理相结合；2.采用靶向代谢组学来定义肿瘤细胞NAD/NADH代谢组在疾病进展和治疗的特定阶段，使用ESI QQQ和NIMS技术，结合XCMS代谢生物信息学；以及3.生成乳腺癌进展阶段的非靶向全面的代谢谱。我们的研究结果可能确定，肿瘤细胞代谢的治疗正常化，例如通过NAD前体治疗，是一种有效、无毒的方法来沉默乳腺癌和防止复发。乳腺癌进展的代谢组将增强该领域的能力，并使基于代谢正常化概念的预防方法的发展成为可能。使用产生的信息的互动和合作努力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.