Targeting Serine Auxotrophy in Luminal Breast Cancer

项目概要/摘要 靶向代谢用于癌症治疗的主要挑战是途径冗余，其中多个途径冗余可能导致癌症。 关键营养素的来源可能会削弱代谢疗法的效果。这方面的一个例子可以在 最近尝试靶向丝氨酸合成途径用于癌症治疗，其中丝氨酸的丰度 可从循环中吸收的丝氨酸阻碍了丝氨酸生物合成抑制剂的成功。这 如果我们希望成功地靶向丝氨酸， 以及其他癌症治疗的关键代谢途径。我们采用了分析人类肿瘤的方法， 基因表达数据，以确定由于谱系依赖性基因而限制途径冗余的情况 表达，从而产生潜在的脆弱性。使用这种方法，我们发现，两个主要的 乳腺肿瘤的谱系--管腔型和基底型--表达水平差异很大的PSAT 1（磷酸丝氨酸 氨基转移酶1），编码丝氨酸合成途径的第二种酶的基因。管腔型乳腺 表达极低水平PSAT 1的癌细胞不能激活丝氨酸合成途径 即使当细胞外丝氨酸完全不存在时。因此，它们完全依赖于外源性 丝氨酸用于增殖和存活。这与基底乳腺癌细胞相反，基底乳腺癌细胞能够合成 丝氨酸，并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 可能是由于PSAT 1基因的管腔特异性甲基化。根据这些数据，我们提出了一个假设， PSAT 1基因的谱系特异性表观遗传沉默诱导管腔型乳腺肿瘤中的丝氨酸营养缺陷型 并使它们容易受到丝氨酸摄取的抑制。在这个建议中，我们将1）确定是否鲁米诺 乳腺肿瘤对体内丝氨酸饥饿敏感，2）确定PSAT 1抑制的机制 在管腔肿瘤中，和3）鉴定和表征丝氨酸转运蛋白作为潜在的药理学靶标， 这种脆弱性。虽然由于使用了化疗，管腔型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， 复发因此，超过一半的乳腺癌死亡是由于管腔乳腺癌，使这一领域 未满足的临床需求。本提案中描述的实验有可能发现新的 晚期管腔型乳腺癌患者的治疗选择。

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.