Regulation of arginine metabolism as a therapeutic target in breast cancer

精氨酸代谢的调节作为乳腺癌的治疗靶点

• 批准号: 9325240
• 负责人: Renee Catherine Geck
• 金额: $ 3.67万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325240
• 关键词: Anabolism; Arginine; Autophagocytosis; Biological Markers; Breast Cancer Cell; Breast Cancer cell line; Breast Cancer therapy; Cancer Cell Growth; Cancer Etiology; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Characteristics; Data; Disease; Drug resistance; Enzymes; Gene Expression Profile; Genes; Genetic Transcription; Goals; Knowledge; Malignant Neoplasms; Measures; Metabolic; Metabolism; Non-Essential Amino Acid; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Primary carcinoma of the liver cells; Regimen; Regulation; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Sirolimus; Starvation; Testing; Therapeutic; Variant; Woman; Xenograft Model; actionable mutation; cancer cell; cancer subtypes; cancer therapy; cell growth; clinical efficacy; combat; improved; inhibitor/antagonist; interest; malignant breast neoplasm; melanoma; new therapeutic target; novel; novel marker; novel therapeutic intervention; response; response biomarker; sensor; targeted treatment; therapeutic biomarker; therapeutic target; therapy resistant; tumor heterogeneity; tumor metabolism; tumor microenvironment

Abstract Cancer cells contain alterations that promote cell growth and survival. One such alteration is aberrant activation of oncogenic signaling pathways. The PI3K/Akt/mTORC1 pathway is altered in nearly 70% of breast cancers, and thus multiple targeted therapies have been developed for use in breast cancers with pathway alterations. However, clinical efficacy has been disappointing, with limited activity from single agents. Additionally, many breast cancers do not contain a single driver mutation, and targeted therapies are unlikely to eliminate all breast cancer cells due to tumor heterogeneity. Interest in studying the relationship between cancer and metabolism has arisen as an avenue to identify novel biomarkers and therapeutic targets that are effective across multiple breast cancer subtypes. These metabolic changes allow cells to survive in the tumor microenvironment. The nonessential amino acid arginine is a candidate for metabolic therapy because it can become essential in cancer cells. Arginine starvation therapy has been effective in arginine auxotrophic cancers, such as malignant melanoma and hepatocellular carcinoma. However, preliminary data suggest that breast cancer cells vary in their sensitivity to arginine starvation, and it is not yet known what determines this varied sensitivity. Our studies also described correlations between resistance to PI3K and Akt inhibitors and alterations in arginine metabolism, indicating that PI3K/Akt/mTORC1 signaling may be related to the regulation of arginine metabolism in breast cancer. I hypothesize that the different requirements for arginine-derived metabolites across breast cancer cell lines can be exploited to inhibit breast cancer cell growth and survival. The goal of this proposal is to determine how arginine availability leads to changes in arginine metabolism, and how these changes can be targeted to decrease breast cancer cell viability in specific cellular settings. I first aim to classify breast cancer cell lines by their responses to arginine, and identify differences between these cells lines that can be used as novel therapeutic targets or biomarkers for sensitivity to arginine starvation therapy. In my second aim, I will investigate the role of mTORC1 signaling as an arginine sensor to determine its ability to regulate arginine metabolism. Finally, I will investigate arginine metabolic therapy in the context of breast cancer cells that are resistant to PI3K/Akt inhibitors. Determining variations that account for different responses to arginine, including mTORC1-dependent responses, will broaden our knowledge of metabolic regulation. It will also identify novel therapeutic targets and biomarkers for response to arginine metabolic therapy in breast cancer, increasing our ability to combat this disease, including in drug-resistant settings. As a whole, this project will expand our knowledge of the role of arginine metabolism in breast cancer and its value in therapy.

摘要 癌细胞含有促进细胞生长和存活的改变。其中一种改变是异常的 致癌信号通路的激活。PI 3 K/Akt/mTORC 1通路在近70%的乳腺癌中发生改变。 因此，已经开发了多种靶向疗法用于具有途径的乳腺癌。 改变。然而，临床疗效令人失望，单一药物的活性有限。 此外，许多乳腺癌不包含单一驱动突变，靶向治疗不太可能 以消除所有乳腺癌细胞由于肿瘤异质性。有兴趣研究 癌症和代谢已经成为鉴定新的生物标志物和治疗靶点的途径， 对多种乳腺癌亚型有效。这些代谢变化使细胞能够在肿瘤中存活 微环境。非必需氨基酸精氨酸是代谢治疗的候选者，因为它可以 在癌细胞中变得至关重要。精氨酸饥饿疗法对精氨酸营养缺陷型 癌症，如恶性黑素瘤和肝细胞癌。然而，初步数据显示， 乳腺癌细胞对精氨酸饥饿的敏感性不同，目前还不知道是什么决定了这一点 不同的敏感度。我们的研究还描述了对PI 3 K和Akt抑制剂的抗性之间的相关性， 精氨酸代谢的改变，表明PI 3 K/Akt/mTORC 1信号可能与调节 精氨酸在乳腺癌中的代谢。我推测，对精氨酸衍生物的不同要求 可以利用跨乳腺癌细胞系的代谢物来抑制乳腺癌细胞生长和存活。 本提案的目的是确定精氨酸的可用性如何导致精氨酸的变化 代谢，以及这些变化如何能够靶向降低乳腺癌细胞在特定细胞中的生存力。 设置.我的第一个目标是通过对精氨酸的反应来对乳腺癌细胞系进行分类， 在这些细胞系之间，可以用作对精氨酸敏感性的新的治疗靶点或生物标志物， 饥饿疗法在我的第二个目标中，我将研究mTORC 1信号作为精氨酸传感器的作用， 确定其调节精氨酸代谢的能力。最后，我将研究精氨酸代谢治疗在 乳腺癌细胞对PI 3 K/Akt抑制剂具有抗性。 确定导致对精氨酸的不同反应的变异，包括mTORC 1依赖性 反应，将扩大我们对代谢调节的认识。它还将确定新的治疗靶点 和生物标志物对乳腺癌精氨酸代谢治疗的反应，提高我们对抗 这种疾病，包括在耐药性环境中。作为一个整体，这个项目将扩大我们的知识的作用， 精氨酸代谢在乳腺癌中的作用及其在治疗中的价值。