Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G‑Quadruplex-Binding Small Molecule

Human pancreatic ductal adenocarcinoma
(PDAC) involves the dysregulation
of multiple signaling pathways. A novel approach to the treatment
of PDAC is described, involving the targeting of cancer genes in PDAC
pathways having over-representation of G-quadruplexes, using the trisubstituted
naphthalene diimide quadruplex-binding compound 2,7-bis­(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)­ethyl)­amino)­benzo­[lmn]­[3,8]­phenanthroline-1,3,6,8­(2H,7H)-tetraone (CM03). This compound has been designed by computer
modeling, is a potent inhibitor of cell growth in PDAC cell lines,
and has anticancer activity in PDAC models, with a superior profile
compared to gemcitabine, a commonly used therapy. Whole-transcriptome
RNA-seq methodology has been used to analyze the effects of this quadruplex-binding
small molecule on global gene expression. This has revealed the down-regulation
of a large number of genes, rich in putative quadruplex elements and
involved in essential pathways of PDAC survival, metastasis, and drug
resistance. The changes produced by CM03 represent a global response
to the complexity of human PDAC and may be applicable to other currently
hard-to-treat cancers.

人类胰腺导管腺癌（Human pancreatic ductal adenocarcinoma, PDAC）存在多条信号通路的失调。本文报道了一种针对PDAC的新型治疗策略：通过靶向PDAC通路中富含G-四链体（G-quadruplexes）的癌症基因，使用三取代萘二酰亚胺类四链体结合化合物2,7-双(3-吗啉代丙基)-4-((2-(吡咯烷-1-基)乙基)氨基)苯并[lmn][3,8]菲咯啉-1,3,6,8(2H,7H)-四酮（CM03）。该化合物经计算机建模设计而成，对PDAC细胞系具有强效的细胞生长抑制活性，并在PDAC模型中展现出抗癌活性，其疗效优于临床常用治疗药物吉西他滨（gemcitabine）。研究采用全转录组RNA测序（Whole-transcriptome RNA-seq）技术分析该四链体结合小分子对全局基因表达的影响，结果显示大量携带有潜在四链体元件、且参与PDAC生存、转移及药物耐药核心通路的基因出现下调。CM03诱导的基因表达变化代表了针对人类PDAC复杂性的全局应答，或可推广应用于其他当前难以治疗的癌症。