Molecular Profiling of Pancreatic Cancer

胰腺癌研究的主要挑战之一是从接受手术切除的患者中获得具有完整人口统计学和临床病理学信息的临床样本。我们临床样本的主要来源是通过NCI-University of马里兰州的人类致癌实验室资源合同。此外，通过我们在世界各地的合作，我们正在建立一个国际胰腺癌队列联盟，用于我们的研究。这些标本将成为我们胰腺癌研究的宝贵财富。使用全局策略，通过mRNA和miRNA表达以及代谢物谱分析胰腺导管腺癌（PDAC）样品。mRNA和miRNA表达谱的分析鉴定了与患者结果相关的基因，并且可能有助于疾病侵袭性和对可用疗法的抗性。这些候选基因在PDAC的独立队列中得到进一步验证，并且已经检查了它们在肿瘤进展和化疗耐药性中的机制作用。简单地说，我们发现肿瘤中DPEP 1（二肽酶1）的低表达与两个独立的手术切除患者队列中的生存率差相关，并且与分期和切除边缘状态无关。在两个队列中，与来自同一患者的非肿瘤胰腺相比，肿瘤中的DPEP 1表达显著较低。胰腺癌细胞系Panc 1中DPEP 1的过表达抑制了细胞的迁移和侵袭，并增加了对一线治疗胰腺癌药物吉西他滨的敏感性。鉴于这些发现，我们建议DPEP 1可能是一个有用的目标，在设计一个改进的治疗策略。这些调查结果正在提交出版。我们目前正在分析mRNA和miRNA表达谱和代谢组学数据，以确定PDAC的分子亚型，这决定了患者的预后。为了实现本项目的第二个目标，我们将继续努力完成一项方案和问卷调查，以启动一项由我本人担任主要研究者的大巴尔的摩地区胰腺癌病例对照研究。我们对病例对照研究的概念提案已由NCI医学肿瘤学分支科学审查委员会进行了早期审查。尽管委员会承认拟议的研究对于解决目前未满足的PDAC早期检测和有效治疗的临床需求非常重要，但由于规定和建议，批准被推迟。该提案正在修订中，以便重新提交。

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. Our primary source of clinical samples is through the NCI-University of Maryland Resource Contract of the Laboratory of Human Carcinogenesis. In addition, through our collaboration around the world, we are establishing an International Consortium of pancreatic cancer cohorts to be used in our studies. This collection will be an invaluable asset for our pancreatic cancer studies. Using a global strategy, pancreatic ductal adenocarcinoma (PDAC) samples were analyzed by mRNA and miRNA expression, and metabolite profiling. Analysis of mRNA and miRNA expression profile identified genes that are associated with patients outcome and may contribute to disease aggressiveness and resistance to available therapy. These candidate genes are further validated in independent cohorts of PDAC and their mechanistic role in tumor progression and chemoresistance has been examined. Briefly, we found that a lower expression of DPEP1 (dipeptidase 1) in tumor was associated with poor survival in two independent cohorts of surgically resected patients and was independent of stage and resection margin status. DPEP1 expression was significantly lower in tumors as compared to non-tumor pancreas from the same patient in both the cohorts. Overexpression of DPEP1 in pancreatic cancer cell line Panc1 inhibited cell migration and invasion, and increased the sensitivity to gemcitabine, a first-line drug for treating pancreatic cancer. In view of these findings, we propose that DPEP1 may be a useful target in designing an improved therapeutic strategy. These findings are being submitted for publication. We are currently analyzing mRNA and miRNA expression profiling and metabolomics data to identify molecular subtypes of PDAC, which dictates patients outcome. To move towards our second goal of this project, we are continuing our efforts of finalizing a protocol and questionnaire to initiate a case-control study of pancreatic cancer in the greater Baltimore area with myself as the Principal Investigator. Our concept proposal for the case-control study has been earlier reviewed by the NCI, Medical Oncology Branch Scientific Review Committee. Although committee acknowledged that the proposed study is very important to address the current unmet clinical needs of early detection and effective treatment in PDAC, the approval is deferred with stipulations and recommendations. The proposal is being revised for resubmission.