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: 8858765
• 负责人: Brunhilde H. Felding
• 金额: $ 11.29万
• 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/8858765
• 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 metabolism; tumor microenvironment; 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.

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，这一信息转化为一种新策略，其中通过 NAD 前体治疗使 NAD+/NADH 氧化还原平衡正常化，从而抑制异种移植模型中的肿瘤生长和转移性疾病，并在癌基因驱动的转基因模型中干扰乳腺癌进展。 自发性乳腺癌。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将有助于降低乳腺癌患者的死亡率。