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

使乳腺癌代谢正常化以防止进展和复发 (PQ21)

• 批准号: 8384789
• 负责人: Brunhilde H. Felding
• 金额: $ 46.79万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384789
• 关键词: Address; Adjuvant Therapy; Affect; Animal Model; Appearance; Automobile Driving; Bioinformatics; Biology; Breast Cancer Cell; Cancer Etiology; Cancer Patient; Cessation of life; Characteristics; Clinic; Clinical; Complex; Cytotoxic Chemotherapy; Development; Disease; Disease Progression; Equilibrium; Event; Growth; Image; Informatics; Lead; Learning; Lesion; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; NADH; Nanostructures; Nature; Nutrient; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxygen; Pathway interactions; Patients; Penetration; Preventive; Radiation therapy; Radiosurgery; Recurrence; Relapse; Residual Tumors; Resistance; Risk; Specimen; Staging; Symptoms; Technology; Therapeutic; Tissue Sample; Transgenic Mice; Transgenic Model; Translating; Woman; Xenograft Model; Xenograft procedure; base; cancer care; cancer stem cell; cancer surgery; cancer therapy; cell killing; chemotherapy; empowered; improved; killings; malignant breast neoplasm; meetings; metabolomics; mortality; mouse model; neoplastic cell; novel therapeutics; pressure; prevent; response; standard of care; stem; therapeutic target; tumor; tumor growth; tumor progression

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.

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，从而导致很高的死亡率。尽管手术和治疗取得了进步，但护理标准仍然主要依赖于旨在杀死肿瘤细胞的化疗和放射疗法。进化模型预测，这些方法施加的选择压力会导致耐药克隆存活，最终重新激活疾病。基于代谢肿瘤细胞改变在癌症中的核心参与，本申请遵循以下原则： 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，而是实现并维持无疾病症状的状态。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总体结果产生革命性影响。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，该信息转化为一种新策略，即通过 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性疾病，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，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疗效，包括与标准护理相结合； 2. 利用ESI QQQ和NIMS技术，结合XCMS代谢组生物信息学，采用靶向代谢组学，明确疾病进展和治疗特定阶段的肿瘤细胞NAD+/NADH代谢组； 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、无毒的方法来抑制乳腺癌并预防复发。乳腺癌进展的代谢组学将赋予该领域力量，并促进基于代谢正常化概念的预防方法的开发。使用生成的信息进行互动和协作努力将有助于降低乳腺癌患者的死亡率。 公共健康相关性：该项目解决了 NCI 的挑衅性问题 PQ21：“鉴于细胞杀伤疗法出现耐药性，我们能否通过使用保持肿瘤静态的方法来延长生存期？”尽管乳腺癌手术和治疗有所改进，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该疾病经常复发，通常是在最初的辅助治疗明显成功后数年。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射疗法。然而，这些治疗很可能会选择更具侵袭性的肿瘤细胞，最终重新激活疾病并对治疗产生耐药性。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，无论最初的转化事件和疾病驱动机制如何，乳腺癌细胞都依赖于改变的代谢回路，使肿瘤细胞能够满足其能量需求，不仅可以加速生长，而且可以在营养和氧气获取方式发生变化的情况下生存在肿瘤微环境的生态位内。根据我们的结果以及代谢肿瘤细胞改变在疾病进展中的核心参与，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，这种方法不会根除所有残留疾病，而是实现并维持临床疾病无症状状态。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，因此不利于可能导致复发的逃逸克隆或癌症干细胞的渗透。因此，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总体结果产生革命性影响。