Understanding Sex Disparities in Gliomas Through Sex Differences in Mitochondrial Activity

项目主任/主要研究者（最后，第一，中间）：Ippolito，Joseph Edward 项目摘要 在全身癌症中存在性别差异，男性的发病率较高， 死亡率高于女性。这不仅适用于成年人，也适用于儿童，这表明 除了性激素的影响之外，其他因素也可能在这一现象中发挥作用。这是特别 胶质母细胞瘤（GBM）占脑肿瘤的50%以上，其特征是对 治疗和预后不佳（中位生存期-15个月）。因为营养素消耗的增加， 代谢对于增强肿瘤发生及其对不良患者结局的影响至关重要，我们的研究小组 研究了癌症代谢中存在的性别差异，这种差异可能导致性别差异， 在许多癌症中观察到。我们已经发现了实验室和临床证据表明，男性 脑肿瘤具有增强的营养摄取和代谢（特别是糖和氨基酸）， 女性肿瘤我们进一步确定，癌症代谢中最大的性别差异来自于 线粒体，细胞的一部分，是产生能量和生物合成的基石， 细胞生长。因为代谢不仅限于肿瘤，而是涉及整个患者，我们有 研究了营养和肥胖的性别差异对癌症患者生存的影响。我们已经发现 有“男性模式”增加的内脏腹部肥胖的女性选择性地比所有女性做得更差。 其他癌症患者。这些发现表明，我们在癌症中看到的性别差异可能 不仅与肿瘤线粒体有关，而且与个体的营养及其整体代谢健康有关。在这 建议，我们将开发新的动物模型来测试线粒体活性的性别差异的假设， 肿瘤发展的性别差异。我们的长期目标是了解性的代谢基础 通过肿瘤和宿主代谢的组合，在癌症患者中产生差异。第一个目标是 我们将使用已建立的模型（Nf 1-/-/DNp 53）来研究GBM的性别差异，并耗尽线粒体 在癌细胞中测试癌细胞表型和代谢的性别差异。第二个目标，我们 将确定致肥饮食对脑肿瘤线粒体活性和生长的性别差异的影响。 这项研究提案具有创新性，因为它在肿瘤学领域开辟了一个新的范式， 癌症和宿主代谢的性别特异性差异。这一建议将产生新的见解 线粒体活性性别差异背后的机制以及营养对线粒体性别差异的影响 恶性表型我们正在开始开发一个新的易于翻译的成像方法平台 和治疗方法，不仅治疗脑肿瘤，但多种恶性肿瘤。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码

Program Director/Principal Investigator (Last, First, Middle): Ippolito, Joseph Edward PROJECT SUMMARY There is a sex disparity seen in cancers throughout the body where males have both a higher incidence and a higher mortality than females. This is not only true for adults, but is also seen in children as well, suggesting that factors other than the effects of sex hormones may be playing a role in this phenomenon. This is especially true for glioblastomas (GBM) that comprise over 50% of brain tumors and are characterized by resistance to therapies and a dismal prognosis (median survival - 15 months). Because enhanced nutrient consumption and metabolism are critical to enhanced tumorigenesis and its effect on poor patient outcomes, our group investigates the presence of sex differences in cancer metabolism that may be driving the sex disparities that are observed in many cancers. We have uncovered laboratory and clinical evidence demonstrating that male brain tumors have enhanced nutrient uptake and metabolism (specifically sugars and amino acids) compared to female tumors. We have further identified that the largest sex differences in cancer metabolism come from the mitochondria, the part of the cell that is the critical for generating energy and biosynthetic building blocks for the cell for growth. Because metabolism is not only restricted to the tumor, but involves the entire patient, we have investigated the effects of sex differences in nutrition and obesity in cancer patient survival. We have discovered that women with “male-pattern” increased visceral abdominal obesity selectively do much worse compared to all other patients in multiple cancers. These findings suggest that the sex differences that we see in cancers may not only be related to tumor mitochondria, but nutrition and its overall metabolic health of the individual. In this proposal, we will develop new animal models to test the hypothesis that sex differences in mitochondrial activity underlie sex differences in tumor development. Our long term goal is to understand the metabolic basis of sex disparities in cancer patients through a combination of tumor and host metabolism. In the first aim of this proposal, we will use an established model (Nf1-/-/DNp53) for sex differences in GBM and deplete mitochondria in the cancer cells to test for sex differences in cancer cell phenotype and metabolism. In the second aim, we will determine the effects of obesogenic diets on sex differences in brain tumor mitochondrial activity and growth. This research proposal is innovative because it opens up a new paradigm in the oncology field that investigates sex-specific differences in cancer and host metabolism. This proposal will generate new insights into the mechanism behind sex differences in mitochondrial activity and the impact of nutrition on sex differences in the malignant phenotype. We are beginning to develop a platform for novel readily-translatable imaging methods and therapeutic approaches that treat not only brain tumors, but multiple malignancies. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page