Molecular Profiling of Pancreatic Cancer

胰腺癌研究的主要挑战之一是获得手术切除患者的临床样本，并提供完整的人口学和临床病理信息。在我们持续不断的努力中，我们已经成功地建立了从美国和国外的病例中切除的胰腺癌样本的多个队列。这包括一项新的批准的研究方案，即在我担任首席研究员的情况下，从大巴尔的摩地区的500例PDAC病例中收集肿瘤和/或血液样本。这些藏品将是我们胰腺癌计划的无价资产。我们的先导基因表达谱研究结果表明，DPEP1(二肽酶1)在肿瘤中的低表达与两个独立的PDAC队列中较差的生存相关，并且与分期和切除切缘状态无关(Zhang Et)。等，《公共科学图书馆·综合》，2012年)。在两个队列中，与来自同一患者的邻近非肿瘤胰腺相比，DPEP1在肿瘤中的表达显著降低。DPEP1在胰腺癌细胞株中的过表达抑制了细胞的迁移和侵袭，并增加了对治疗胰腺癌的一线药物吉西他滨的敏感性。我们还发现，DPEP1受EGF/MEK/MAPK通路的调控，MEK1/2抑制剂在体外促进了DPEP1的表达。鉴于这些发现，我们认为，通过新的方法重新表达DPEP1可能有助于PDAC的治疗，以提高患者的存活率。目前，我们正在验证DPEP1在体内抑制肿瘤进展的假设。在我们继续研究与疾病侵袭性相关的肿瘤生物学的过程中，我们目前正在比较两组切除患者的肿瘤基因表达谱：一组患者生存期较短(7个月)，另一组患者术后生存期较长(24-70个月)，并进一步验证以下假设：a)炎症基因推动切除患者的肿瘤侵袭性，b)炎症相关基因特征定义可切除PDAC中的侵袭性亚型。

One of the major challenges in pancreatic cancer research is the availability of clinical samples from patients undergoing surgical resection with complete demographic and clinico-pathological information. In our ongoing efforts, we have been successful in establishing multiple cohorts of resected pancreatic cancer samples from cases in the United States and abroad. This includes a new approved study protocol to collect tumors and/or blood samples from 500 PDAC cases in the greater Baltimore area with myself as principal investigator. This collection will be an invaluable asset for our pancreatic cancer program. The results from our pilot gene-expression profiling study showed that a lower expression of DPEP1 (dipeptidase 1) in tumors was associated with poorer survival in two independent cohorts of PDAC and was independent of stage and resection margin status (Zhang et. al., PLoS One, 2012). DPEP1 expression was significantly lower in tumors as compared to adjacent non-tumor pancreas from the same patient in both the cohorts. Overexpression of DPEP1 in pancreatic cancer cell lines inhibited cell migration and invasion, and increased the sensitivity to gemcitabine, a first-line drug for treating pancreatic cancer. We also showed that DPEP1 is regulated by EGF/MEK/MAPK pathway, and MEK1/2 inhibitor enhanced DPEP1 expression in vitro. In view of these findings, we propose that re-expression of DPEP1 by novel approaches could be useful for the treatment of PDAC in improving patient survival. Currently, we are testing the hypothesis that DPEP1 inhibits tumor progression in vivo. In our continuing effort of examining the tumor biology associated with disease aggressiveness, we are currently comparing the gene expression profile of tumors in two groups of resected patients: one with a short survival (<7 months) and the other with a longer survival (24-70 months) following resection, and further testing the hypotheses that a) Inflammatory genes drive tumor aggressiveness in resected patients and b) Inflammation-associated gene signature defines aggressive subtypes in resectable PDAC.