Uncovering Mechanisms of Regulation and Dependency on Fatty Acid Oxidation in MYC-Driven Tumors

项目摘要 MYC癌基因在一些最具侵袭性和难以治疗的人类癌症中过表达， 包括受体三阴性乳腺癌（TNBC），以及高级别淋巴瘤和侵袭性乳腺癌。 肝癌的亚型。MYC过表达通过驱动增殖诱导高度恶性状态， 改变肿瘤细胞内的各种代谢程序。我们最近发现MYC驱动的转基因 乳腺癌模型已经重新编程了有利于脂肪酸氧化（FAO）的细胞代谢， 能源。这一发现也在MYC-高TNBC中观察到，并且最近得到了一项研究的证实。 独立研究小组。在人类细胞系、MYC驱动的转基因动物模型和 患者来源的乳腺癌异种移植物（PDX）模型导致肿瘤生长减少和细胞增殖增加。 死亡目前尚不清楚的是，MYC通过何种分子机制重新编程肿瘤细胞， 有利于粮农组织的新陈代谢。此外，我们试图理解为什么MYC高肿瘤依赖于 粮农组织的发展和生存之路。最后，我们寻求通过以下方式改进目前的TNBC疗法： 在PDX模型中进行先进的临床前研究，以确定是否单独或联合阻断FAO 与体内其他代谢途径的结合将提供改善的治疗反应。我们的学习将提高我们的 了解MYC如何在体内重新编程代谢，并将导致难以治疗的新疗法。 治疗MYC过度表达的癌症。

Project Summary The MYC oncogene is overexpressed in some of the most aggressive and difficult to treat human cancers, including receptor triple-negative breast cancers (TNBCs), as well as high-grade lymphomas and aggressive subtypes of liver cancers. MYC overexpression induces a highly malignant state by driving proliferation and altering various metabolic programs within tumor cells. We recently discovered that MYC-driven transgenic models of breast cancer have reprogramed cellular metabolism that favor fatty acid oxidation (FAO) as an energy source. This finding was also observed in MYC-high TNBCs and has recently been confirmed by an independent research group. Targeting FAO in human cell lines, MYC-driven transgenic animal models and patient-derived xenograft (PDX) models of breast cancer results in diminished tumor growth and increased cell death. What remains unknown is what are the molecular mechanisms through which MYC reprograms tumor metabolism to favor FAO. Furthermore, we seek to understand why MYC-high tumors are dependent on the FAO pathway for their growth and survival. Finally, we seek to improve upon current therapies for TNBCs by performing advance preclinical studies in PDX models to determine if blocking FAO alone or in combination with other metabolic pathways in vivo will provide improved therapeutic response. Our studies will improve our understanding of how MYC reprograms metabolism in vivo and will lead to novel therapeutics for difficult to treat MYC overexpressing cancers.