Targeting Serine Auxotrophy in Luminal Breast Cancer

靶向管腔乳腺癌中的丝氨酸营养缺陷型

• 批准号: 10209007
• 负责人: Jonathan L. Coloff
• 金额: $ 35.97万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209007
• 关键词: Acute T Cell Leukemia; Address; Amino Acids; Anabolism; Area; Asparagine; Biological Markers; Blood Circulation; Breast Cancer Cell; Breast Cancer Patient; Cancer Patient; Cells; Clinical; Data; Diet; Disease Resistance; Environment; Enzymes; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Human; In Vitro; Knowledge; Lead; Mammary Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methylation; Mus; Non-Essential Amino Acid; Normal tissue morphology; Nutrient; Outcome; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphoserine aminotransferase; Positioning Attribute; Prognosis; Proliferating; Relapse; Research; Resistance development; Resources; Serine; Source; Starvation; Testing; Therapeutic; Translating; Tumor Tissue; amino acid metabolism; asparaginase; auxotrophy; base; cancer cell; cancer therapy; dietary; epigenetic silencing; experience; experimental study; extracellular; hormone therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; metabolic phenotype; novel; novel therapeutics; prevent; prospective; side effect; standard of care; success; targeted cancer therapy; therapeutic target; therapy resistant; tumor; tumor metabolism; tumor xenograft; uptake

PROJECT SUMMARY/ABSTRACT A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple sources of critical nutrients can diminish the effects of metabolic therapies. An example of this can be found in recent attempts to target the serine synthesis pathway for cancer therapy, where the abundance of serine available to be taken up from the circulation has hampered the success of inhibitors of serine biosynthesis. This places a premium on pursuing strategies of limiting pathway redundancy if we wish to successfully target serine and other critical metabolic pathways for cancer therapy. We have taken the approach of analyzing human tumor gene expression data to identify scenarios where pathway redundancy is limited due to lineage-dependent gene expression, thereby creating potential vulnerabilities. Using this approach, we have found that the two major lineages of breast tumors—luminal and basal—express vastly different levels of PSAT1 (phosphoserine aminotransferase 1), the gene encoding the second enzyme of the serine synthesis pathway. Luminal breast cancer cells, which express extremely low levels of PSAT1, are unable to activate the serine synthesis pathway even when extracellular serine is completely absent. As a result, they are entirely dependent on exogenous serine for proliferation and survival. This is in contrast to basal breast cancer cells, which are able to synthesize serine and proliferate in the absence of extracellular serine. Mechanistically, this serine auxotrophy appears to be due to luminal-specific methylation of the PSAT1 gene. Based on this data, we have developed the hypothesis that lineage-specific epigenetic silencing of the PSAT1 gene induces serine auxotrophy in luminal breast tumors and makes them vulnerable to inhibition of serine uptake. In this proposal, we will 1) determine whether luminal breast tumors are sensitive to dietary serine starvation in vivo, 2) define the mechanism of PSAT1 suppression in luminal tumors, and 3) identify and characterize serine transporters as potential pharmacological targets of this vulnerability. While luminal breast cancer patients initially have a favorable prognosis due to the utility of endocrine therapies, over half of all patients eventually develop resistance to these therapies and undergo relapse. As a result, over half of all breast cancer fatalities are due to luminal breast cancer, making this an area of significant unmet clinical need. The experiments described in this proposal have the potential to identify new therapeutic options for patients with advanced luminal breast cancer.

项目概要/摘要 癌症治疗靶向代谢的一个主要挑战是通路冗余，其中多个 关键营养素的来源会削弱代谢疗法的效果。 最近尝试针对癌症治疗的丝氨酸合成途径，其中丰富的丝氨酸 可从循环中吸收阻碍了丝氨酸生物合成抑制剂的成功。 如果我们希望成功地靶向丝氨酸，则应重视采取限制途径冗余的策略 以及癌症治疗的其他关键代谢途径我们采用了分析人类肿瘤的方法。 基因表达数据，用于识别由于谱系依赖性基因而导致通路冗余受到限制的情况 表达式，从而产生潜在的漏洞，使用这种方法，我们发现了两个主要的漏洞。 乳腺肿瘤谱系（管腔肿瘤和基底肿瘤）表达的 PSAT1（磷酸丝氨酸）水平差异很大 转氨酶 1)，编码 Luminal 乳腺丝氨酸合成途径的第二种酶的基因。 表达极低水平 PSAT1 的癌细胞无法激活丝氨酸合成途径 即使细胞外丝氨酸完全不存在，它们也完全依赖于外源性。 这与能够合成丝氨酸的基底乳腺癌细胞相反。 丝氨酸在缺乏细胞外丝氨酸的情况下增殖。从机制上讲，这种丝氨酸营养缺陷型似乎是这样的。 是由于 PSAT1 基因的管腔特异性甲基化所致。根据这些数据，我们提出了假设。 PSAT1 基因谱系特异性表观遗传沉默可诱导管腔乳腺肿瘤丝氨酸营养缺陷 并使它们容易受到丝氨酸摄取的抑制。在本提案中，我们将 1) 确定是否具有鲁米那。 乳腺肿瘤对体内饮食丝氨酸饥饿敏感，2) 定义 PSAT1 抑制机制 在管腔肿瘤中，3) 识别和表征丝氨酸转运蛋白作为潜在的药理学靶点 由于这种脆弱性，管腔乳腺癌患者最初具有良好的预后。 内分泌治疗，超过一半的患者最终对这些治疗产生耐药性并接受 因此，超过一半的乳腺癌死亡是由于腔内乳腺癌造成的，这使得这一领域成为一个领域。 该提案中描述的实验有可能发现新的未满足的临床需求。 晚期管腔乳腺癌患者的治疗选择。