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 靶向代谢用于癌症治疗的一个主要挑战是路径冗余，其中多个 关键营养素的来源可能会降低代谢疗法的效果。有关这方面的示例，请参阅 最近针对癌症治疗的丝氨酸合成途径的尝试，其中丰富的丝氨酸 可从循环中获取的物质阻碍了丝氨酸生物合成抑制剂的成功。这 如果我们想要成功地以丝氨酸为靶点，就应该重视限制通路冗余的策略 以及其他癌症治疗的关键代谢途径。我们已经采取了分析人类肿瘤的方法 基因表达数据，用于识别因血统依赖基因而限制路径冗余的场景 表达式，从而造成潜在的漏洞。使用这种方法，我们发现两个主要的 乳腺肿瘤的谱系--管腔和基底--表达的PSAT1(磷酸丝氨酸)水平差异很大 转氨酶1)，编码丝氨酸合成途径的第二种酶的基因。腔内乳房 表达极低水平PSAT1的癌细胞不能激活丝氨酸合成途径 即使胞外丝氨酸完全不存在。因此，它们完全依赖于外源 丝氨酸用于增殖和生存。这与基底乳腺癌细胞形成鲜明对比，后者能够合成 丝氨酸，并在没有胞外丝氨酸的情况下增殖。从机制上讲，这种丝氨酸营养不良似乎 可能是由于PSAT1基因的管腔特异性甲基化所致。基于这些数据，我们提出了假设 PSAT1基因的谱系特异性表观遗传沉默诱导管腔乳腺肿瘤中的丝氨酸营养不良 并使它们容易受到丝氨酸摄取的抑制。在这份提案中，我们将1)确定卢米纳 乳腺肿瘤对体内饮食丝氨酸饥饿敏感，2)确定了PSAT1抑制的机制 以及3)确定丝氨酸转运体为潜在的药理靶点。 这个漏洞。虽然腔内乳腺癌患者最初有良好的预后，因为有用的 内分泌疗法，超过一半的患者最终对这些疗法产生抵抗力，并接受 旧病复发。因此，超过一半的乳腺癌死亡是由腔内乳腺癌造成的，这使这一地区成为 重大的未得到满足的临床需求。这项提案中描述的实验有可能发现新的 晚期腔内乳腺癌患者的治疗选择。