靶向胰腺癌Plectin蛋白的多肽纳米药物设计及其介导的合成致死抗肿瘤效应研究

Pancreatic cancer has a high degree of malignancy and lack of effective therapeutic drugs. The drug olaparib benefits pancreatic cancer patient with mutant BRCA gene because of its "synthetic lethal" effect, but this group of patient only account for 3%-10%. BET inhibitor and olaparib have shown the "synthetic lethal" effect in tumors with wild-type BRCA gene. However，the toxicity to normal cells restricted their application. In the previous study, we constructed EGFR-targeted self-assembling peptide nanomedicine to treat BRCA mutant pancreatic cancer, which significantly improved the drug distribution in vivo, showed efficacy enhancement and toxicity reduction in orthotopic pancreatic tumor model in mice. Another, we found that the abnormally high expression of the plectin protein on the membrane of pancreatic cancer cells is a great target for nanomedicine. Based on this, we proposed that plectin could be used as a target on pancreatic cancer cell membrane to construct targeted self-assembling peptide nanocarriers co-loading olaparib and BET inhibitor to exert synthetic lethal effect. To prove this, the targeting efficiency and mechanism of the peptide nanomedicine to pancreatic cancer cells as well as the molecular mechanism of synthetic lethal effect will be systematically studied and elucidated. Hence, this study will provide a theoretical and practical basis for treatment of the majority of pancreatic cancer patients with wild-type BRCA gene.

胰腺癌预后极差，且缺乏有效治疗药物。靶向药物奥拉帕尼对BRCA突变型胰腺癌具有“合成致死”效应可使患者获益，但该部分患者仅占3%-10%。BET抑制剂联合奥拉帕尼在BRCA野生型肿瘤中亦显示出合成致死效应，然而对正常细胞的毒性限制了其应用。前期研究中，我们构建了EGFR靶向性多肽纳米药物治疗BRCA突变型胰腺癌，发现药物体内分布显著改善，在小鼠胰腺癌模型中显示出增效减毒的抗肿瘤效果。我们发现胰腺癌细胞膜表面异常高表达的Plectin蛋白是纳米药物的良好靶点。基于此，本课题提出以Plectin为靶点构建靶向性自组装多肽纳米载体，可解决药物靶向性问题，联合载运奥拉帕尼与BET抑制剂产生合成致死效应，实现对胰腺癌细胞的精准杀伤。系统研究并阐明该多肽纳米药物在体内外对胰腺癌细胞的靶向效率和机理以及合成致死效应的分子生物学机制，为绝大多数BRCA野生型胰腺癌的纳米药物靶向治疗提供理论和实验基础。

胰腺癌是预后最差的消化道肿瘤，患者总体5年生存率约为8%。近期，PARP抑制剂Olaparib针对BRCA突变胰腺癌的研究结果为靶向治疗胰腺癌带来了希望。然而BRCA突变在所有胰腺癌患者中的比例﹤10%，为使非BRCA突变胰腺癌患者亦能受益于PARP抑制剂的治疗，课题组在前期对BRCA突变型胰腺癌靶向治疗研究的基础上，通过设计特异性更高的靶向性多肽纳米载体，以最佳配比递送Olaparib与BET抑制剂JQ1。体内外研究均表明，该体系具有良好的肿瘤靶向能力，能够特异性地将两种药物递送至肿瘤局部，实现对肿瘤细胞的靶向“围剿”策略。通过小鼠胰腺癌原位模型和人源肿瘤异种移植(PDX)模型，证实该体系对非BRCA突变胰腺癌具有较强的抑瘤效果，并能有效地降低联合用药的毒副作用，为该策略在占胰腺癌90%以上的非BRCA突变胰腺癌患者中的临床应用奠定了实验基础，具有良好的应用前景。