Employing mouse models to translate early detection of pancreas cancer

 描述(申请人提供)：胰腺导管腺癌(PDAC)是最致命和进展最快的癌症之一，预计生存3-6个月，通过目前的治疗方法最小限度地改善。因此，我们面临着对这种癌症有效治疗的新策略的迫切需要。我们未能显著影响患者生存的一个原因通常是由于胰腺癌的晚期诊断。基于临床症状的早期诊断一直是一个挑战，因为在患者发展为侵袭性和侵袭性疾病之前，无症状疾病的病程一直是一个挑战。如果胰腺癌在早期被诊断出来，手术和其他干预措施可能会对改善这种疾病的预后产生重大影响。不幸的是，目前还没有可能挽救生命的非侵入性、敏感和特异的早期检测方法。我们在这方面的努力导致发现GPC1作为存在于早、晚期胰腺癌患者血清外切体上的特异性生物标记物。对197例胰腺癌患者、100例正常人和26例胰腺非肿瘤性疾病患者手术前血清100微升进行盲法分析，发现GPC1+外切体在胰腺癌患者中具有100%的特异性和敏感性，其中包括7例先兆病变(早期胰腺上皮内肿瘤(Panin)和导管内乳头状粘液性肿瘤(IPMN)病变)。重要的是，CA-19-9的血清检测效果较差，不能区分癌症引起的胰腺病变和非癌症病因的胰腺病变。成功验证假定的血清生物标记物需要进行彻底的临床前表征，以确定特定的实用窗口，并探索结合非侵入性成像以提高疗效的益处。在这项计划中，我们将使用PDAC的基因工程小鼠模型进行横断面和纵向研究，将肿瘤的组织学分级、外显子衍生的DNA/RNA的遗传分析和非侵入性MRI结合在一起，目的是建立GPC1+血清外显子在胰腺癌可靠早期检测中的应用。此外，这种方法还可以对治疗后/后续疾病评估/负担进行可靠的监测。通过结合无创性MRI作为基于GCP1+血清外切体检测胰腺癌的验证，我们希望确定一种信息丰富且临床有用的胰腺癌早期诊断系统。这些努力可能会为我们的患者提供早期和有效的治疗选择。

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest and fastest progressing cancers, with a 3 to 6 month expected survival that minimally improves with current therapies. Therefore, we are facing an urgent need for new strategies for effective therapies for this cancer. One reason for our failure to significantly impct patient survival is often due to late stage diagnosis of pancreas cancer. Early diagnosis based on clinical symptoms has been a challenge due to the symptom-free disease course until patients develop aggressive and invasive disease. Surgical and other interventions could have a significant impact on improving the outcome of this disease if pancreatic cancer is diagnosed at an early stage. Unfortunately, potentially life saving non-invasive, sensitive and specific early detection methods are currently not available. Our efforts in this area led to the discovery of glypican-1 (GPC1) as specific biomarker present on serum exosomes of patients with early and late stage pancreatic cancer. Performing blinded analysis of 100 microliters of serum from 197 patients with pancreatic cancer before surgical resection of tumors, 100 normal individuals and 26 patients with non-neoplastic diseases of the pancreas, we were able to detect GPC1+ exosomes with 100% specificity and sensitivity in patients with pancreas cancer, including 7 patients with precursor lesions (early pancreatic intraepithelial neoplastic (PanIN) and intraductal papillary mucinous neoplastic (IPMN) lesions). Importantly, serum assay for CA- 19-9 performed less effectively and could not distinguish between pancreatic lesions due to cancer and non-cancer etiology. Successful validation of putative serum biomarkers requires a thorough pre-clinical characterization to identify specific windows of utility and to explore the benefit of combining non-invasive imaging to increase efficacy. In this proposal, we will employ genetically engineered mouse models of PDAC to perform cross-sectional and longitudinal studies that couple histological grading of tumors, genetic analysis of exosomes derived DNA/RNA and non-invasive MRI with the goal of establishing the utility of GPC1+ serum exosomes for reliable early detection of pancreatic cancer. Additionally, such method could also allow for reliable monitoring of post treatment/follow-up disease assessment/burden. By coupling non-invasive MRI as a validation of GCP1+ serum exosomes-based detection of pancreatic cancer, we hope to identify an informative and clinically useful diagnostic system for early detection of pancreatic cancer. Such efforts may enable early and effective therapy options for our patients.