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: 10570205
• 负责人: Jonathan L. Coloff
• 金额: $ 35.25万
• 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/10570205
• 关键词: Acute T Cell Leukemia; Address; Amino Acids; Anabolism; Area; Asparagine; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Cancer Patient; Cells; Circulation; Clinical; Data; Diet; Disease Resistance; Disparity; Environment; Enzymes; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Human; In Vitro; Knowledge; Mammary Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methylation; Mus; Non-Essential Amino Acid; Normal tissue morphology; Nutrient; Outcome; Pathway interactions; Patients; 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; cancer cell; cancer therapy; candidate identification; dietary; epigenetic silencing; experience; experimental study; extracellular; hormone therapy; in vivo; inhibitor; malignant breast neoplasm; metabolic phenotype; novel; novel therapeutics; pharmacologic; 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.

项目摘要/摘要 靶向代谢进行癌症治疗的主要挑战是途径冗余，其中多个 关键营养素的来源可以减少代谢疗法的影响。一个例子可以在 最新的尝试以癌症的系列合成途径为目标，其中序列化抽象 可从循环中占用的丝氨酸生物合成抑制剂的成功。这 如果我们希望成功针对串行，请备受限制途径冗余的策略的溢价 以及其他关键的癌症治疗代谢途径。我们采取了分析人类肿瘤的方法 基因表达数据以识别由于依赖谱系依赖基因而限制途径冗余的场景 表达，从而产生潜在的漏洞。使用这种方法，我们发现这两个主要 乳腺肿瘤的谱系 - 亮瘤和碱性 - 表达巨大不同水平的PSAT1（磷serine） 氨基转移酶1），编码丝氨酸合成途径的第二个酶的基因。腔乳房 表达极低水平PSAT1的癌细胞无法激活串行合成途径 即使细胞外丝氨酸完全不存在。结果，它们完全取决于外源性 丝氨酸用于增殖和生存。这与能够合成的基本乳腺癌细胞相反 丝氨酸并在没有细胞外丝氨酸的情况下增殖。从机械上讲，这种丝氨酸的合物似乎 是由于PSAT1基因的腔特异性甲基化。基于这些数据，我们开发了假设 PSAT1基因的谱系特异性表观遗传沉默可诱导腔乳腺肿瘤中的丝氨酸一个沉默 并使它们容易受到抑制系列吸收的影响。在此提案中，我们将1）确定是否腔 乳腺肿瘤对体内饮食丝氨酸饥饿敏感，2）定义PSAT1抑制的机制 在腔肿瘤中，3）识别和表征丝氨酸转运蛋白作为潜在的药物靶标 这个脆弱性。腔乳腺癌患者最初由于效用而具有良好的预后 内分泌疗法，超过一半的患者最终对这些疗法产生抗药性并接受 复发。结果，所有乳腺癌死亡的一半以上是由于腔内乳腺癌引起的，使该地区成为 明显未满足的临床需求。本提案中描述的实验有可能识别新的 晚期腔乳腺癌患者的治疗选择。