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Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells

机译：确定靶向胰腺癌转移和癌症干细胞的新型上皮间质转化抑制剂（EMT）

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摘要

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, and it is expected to become the second-leading cause of cancer-related death by 2030. Currently, there are no early detection tests and most patients with localized disease have no recognizable symptoms. As a result, more than half of the patients with this disease are diagnosed at a stage where metastases have developed, for whom the overall 5-year survival is only 2%. Moreover, these tumors are highly enriched with a cancer stem cell (CSC) population (~1%), which is highly resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence.;Recent evidence suggests that epithelial to mesenchymal transition (EMT) is associated with metastasis, generation of CSCs, and treatment resistance in solid tumors including pancreatic cancer. Therefore, compounds inhibiting EMT hold the potential to reverse drug-resistance or inhibit metastasis and CSCs, and therefore could provide better treatment outcome for patients with pancreatic cancer. The overall goal of this dissertation is to investigate novel EMT inhibitors for targeting pancreatic cancer metastasis and CSCs. .;First we demonstrated in preclinical models that treatment with pharmacological doses of ascorbate resulted in inhibition of EMT, metastasis and CSCs. In addition, ascorbate decreased the expression of HDAC6, and inhibited activity of Sirt-2 by depleting NAD+ levels resulting in robustly increased alpha-tubulin acetylation in pancreatic cancer cells. Ascorbate mediated tubulin acetylation promoted ?-tubulin polymerization and stabilization, mimicking the cellular outcomes of paclitaxel to inhibit cancer cell metastasis.;Next, we investigated novel derivatives of the histone deacetylase (HDAC) inhibitors SAHA and MS-275, which are known EMT inhibitors. In an effort to increase efficacy and reduce toxicities of the HDAC inhibitors, we found that the novel synthetic compounds St-1 and St-3 potently inhibited pancreatic cancer cell proliferation and CSCs. St-1 has exhibited similar potency in HDAC inhibition compared to the parent compounds (SAHA and MS-275). Surprisingly, St-3 acted via totally different mechanisms from SAHA and MS-275. St-3 exhibited anti-tumor effects by blocking the interaction of human antigen R (HuR) with its target mRNAs.;Finally, we established and performed a high throughput screening approach to identify inhibitiors of cancer cell EMT. 1-(benzylsulfonyl) indoline (BSI) was found to be a novel EMT inhibitor. BSI significantly inhibited pancreatic cancer cell migration invasion and CSCs. To enhance the efficacy of BSI, several analogues of BSI were tested for their activities on EMT and CSC inhibition. However, BSI analogues failed to show superior anti-migration or anti-CSC activities compare to BSI.;In conclusion, this dissertation resulted in the identification of several novel EMT inhibitors, which can be tested further in preclinical studies for their anti-tumor efficacy.
机译：胰腺癌是美国癌症相关死亡的第四大主要原因，预计到2030年它将成为癌症相关死亡的第二大原因。目前，尚无早期检测测试，并且大多数患有局部疾病的患者没有可识别的症状。结果，超过一半的患有这种疾病的患者被诊断为发生转移的阶段，其总体5年生存率仅为2％。此外，这些肿瘤富含癌干细胞（CSC）群体（〜1％），该群体对化疗药物高度耐药，因此可以逃避化疗并促进肿瘤复发。;最新证据表明上皮向间质转化（EMT） ）与实体瘤（包括胰腺癌）的转移，CSC的产生和治疗抵抗有关。因此，抑制EMT的化合物具有逆转耐药性或抑制转移和CSC的潜力，因此可以为胰腺癌患者提供更好的治疗效果。本文的总体目标是研究针对胰腺癌转移和CSCs的新型EMT抑制剂。首先，我们在临床前模型中证明，用药理学剂量的抗坏血酸盐治疗可抑制EMT，转移和CSC。另外，抗坏血酸通过减少NAD +水平降低了HDAC6的表达，并抑制了Sirt-2的活性，导致胰腺癌细胞中α-微管蛋白的乙酰化大大增加。抗坏血酸介导的微管蛋白乙酰化促进β-微管蛋白的聚合和稳定，模仿紫杉醇抑制癌细胞转移的细胞结局。接下来，我们研究了已知为EMT抑制剂的组蛋白脱乙酰酶（HDAC）抑制剂SAHA和MS-275的新型衍生物。 。为了提高HDAC抑制剂的功效并降低其毒性，我们发现新型合成化合物St-1和St-3有效抑制胰腺癌细胞的增殖和CSC。与母体化合物（SAHA和MS-275）相比，St-1对HDAC的抑制作用相似。令人惊讶的是，St-3通过与SAHA和MS-275完全不同的机制起作用。 St-3通过阻断人类抗原R（HuR）与靶标mRNA的相互作用而表现出抗肿瘤作用。最后，我们建立并进行了高通量筛选方法以鉴定癌细胞EMT的抑制物。发现1-（苄基磺酰基）二氢吲哚（BSI）是新型的EMT抑制剂。 BSI显着抑制胰腺癌细胞迁移侵袭和CSC。为了提高BSI的功效，测试了BSI的几种类似物对EMT和CSC抑制的活性。然而，BSI类似物未能表现出比BSI更好的抗迁移或抗CSC活性。总之，本文确定了几种新型EMT抑制剂，可以在临床前研究中进一步测试其抗肿瘤功效。 。

著录项

  • 作者

    Polireddy, Kishore.;

  • 作者单位

    University of Kansas.;

  • 授予单位 University of Kansas.;
  • 学科 Oncology.;Biology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 169 p.
  • 总页数 169
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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