胰腺癌：进展、挑战及希望

密歇根大学安娜堡分校内科学系消化科转化研究主任、内科助理教授Andrew D. Rhim博士在2014消化疾病周（DDW）ASGE与AGA联席全会上对胰腺癌的进展、挑战和希望进行了评述。

在过去的二十年中，对多种癌症生物学基础的认知取得了巨大进步，死亡率最高的4种癌症（肺癌、结直肠癌、乳腺癌和前列腺癌）的患者生存率得以大幅度提高。与之形成鲜明对比的是，胰腺导管腺癌（PDAC）患者生存率未见显著改变。PDAC是目前导致美国癌症患者死亡的第四大癌症，但预计到2020年，PDAC死亡病例将超过结直肠癌、乳腺癌或前列腺癌，这是因为这一癌症发病率持续增加，而生存时间继续缩短（中位生存时间为6个月）。基于可改善患者中位生存时间2个月，蛋白结合型紫杉醇最近成为FDA多年来批准的首个用于晚期PDAC的药物。

如果希望临床试验能够得出以年度而非以月计算的患者生存时间，那么必须对PDAC生物学基础有一更好的认识。长期以来，对其他癌症研究的经验教训急切地应用于胰腺癌，效果乏善可陈，而患者却付出有害的代价。直到最近，科学家们才全面接受PDAC具有独特的生物学特点的事实。在显微镜下，PDAC看起来有所不同，这是因为存在活跃的促结缔组织增生性反应，活化的成纤维细胞、巨噬细胞和其他炎性细胞与大量结缔组织交织融合。此外，胰腺肿瘤属于独特的少供血肿瘤。

癌细胞长期在缺氧和酸性环境中很可能已经进化为特有的存活机制，产生出对药物具有特殊耐受性的细胞。存活机制之一是向远隔器官传播，并有可能出人意料地出现于PDAC早期。此外，由于肿瘤内部血流有限，全身化疗难以到达肿瘤组织也是PDAC治疗面临的独特和紧迫的问题。

尽管过去我们屡遭失败，但我们已重新调整，再赴征程，并已经做好了向这一疾病发起猛攻的准备。科学家和临床医生最近开发了能够将新发现转化至临床的新工具。新的转基因小鼠模型已经促进了我们对PDAC的了解，并可作为更可靠的新药实验模型。约翰霍普金斯大学Vogelstein及其同事应用先进的测序技术确定PDAC基因组图谱，使得我们能够确认新药靶点，利用最先进的微流体技术开发新的早期诊断方法。其他人员也已经开始应用纳米颗粒载体和其他靶向技术解决PDAC治疗药物传递问题。最后，操控患者免疫系统杀灭初期PDAC细胞是热点研究领域，这或许代表了我们医疗手段中最具希望的治疗策略之一。

经过多年在黑暗中的摸索，我们迎来了新时代——胰腺癌启蒙时代。我们进入了胰腺癌研究空前最有希望的时期，因为我们现在拥有了认知这一疾病的众多新手段。随着对这一疾病的深入了解，我们无疑能够更好地向我们的患者提供他们最需要的东西：以年度而非月份计算的生存期的希望。

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By: ANDREW D. RHIM, M.D.

August 21, 2014

Over the past two decades, remarkable progress has been made in understanding the biological underpinnings of many cancers. Survival of patients with the top four leading causes of cancer deaths in the U.S., carcinomas of the lung, colon and rectum, breast, and prostate, has dramatically increased. In sharp contrast, survival in patients with pancreatic ductal adenocarcinoma (PDAC) has not changed significantly. PDAC is currently the fourth leading cause of cancer death in the U.S., but it is expected to account for more deaths than colorectal, breast, or prostate cancer by 2020, as the incidence of this cancer continues to rise and survival continues to be shockingly brief (median survival of 6 months). Nab-paclitaxel recently became the first FDA-approved drug for advanced PDAC in many years – based on an improvement of 2 months in median survival.

A better understanding of the underlying biology of PDAC is required to even consider the possibility of clinical trials yielding survival on the scale of years as opposed to months. For too long, lessons learned from the study of other cancers have been hastily applied to pancreas cancer, with lackluster results and deleterious costs to our patients. Scientists have only recently fully embraced that the biology of PDAC is unique. Under the microscope, PDAC looks different, owing to an aggressive desmoplastic response – an amalgamation of activated fibroblasts, macrophages and other inflammatory cells admixed with profuse scar tissue. Moreover, pancreas tumors are uniquely hypovascular.

Cancer cells that persist in this cauldron of hypoxia and acidity have likely evolved survival mechanisms that are particular to this disease and produce cells that are particularly resistant to therapy. One such survival mechanism is the ability to seed distant organs; this may occur surprisingly early in the course of PDAC. Furthermore, with limited blood flow within tumors, impaired delivery of systemic chemotherapy is a unique and pressing issue in PDAC.

Despite past failures, our field has recalibrated and rebooted, and we are now poised to make serious inroads against this disease. Scientists and clinicians have recently developed novel tools that will enable new discoveries that will translate to the clinic. Novel, genetically engineered mouse models have catalyzed our understanding of PDAC while also serving as a more faithful model for testing novel drugs. Vogelstein and colleagues at Johns Hopkins utilized advanced sequencing technologies to define the genomic landscape of PDAC, enabling many to identify novel drug targets and develop new assays for early diagnosis utilizing state-of-the-art microfluidic technology. Others have begun to tackle the drug delivery problem in PDAC with nanoparticle vehicles and other targeted modalities. Finally, the manipulation and engineering of the patient\'s immune system to target nascent PDAC cells is an area of intense investigation and represents perhaps one of the most promising therapeutic strategies in our armamentarium.

After many years in the dark, we are poised to enter a new age – an Age of Enlightenment for pancreatic cancer. There is no more promising time for pancreatic cancer research than the present, as we now have a plethora of new tools to understand this disease. And with better understanding, we will undoubtedly be in a better position to deliver to our patients what they sorely need most: hope for survival on the scale of years, as opposed to months.

Dr. Rhim is assistant professor of internal medicine and assistant director for translational research, division of gastroenterology, department of internal medicine, University of Michigan, Ann Arbor. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.