Oncology Frontier: Pancreatic cancer is a highly malignant tumor with high heterogeneity. Molecular targeted drugs and immune treatment have no significant effect， which means the treatment of pancreatic cancer is extremely difficult at present. Could you talk about how we might overcome this dilemma?

　　《肿瘤瞭望》：胰腺癌是一种恶性程度极高的肿瘤，具有高度异质性，主要表现为肿瘤微环境严重纤维化、极度缺氧。针对胰腺癌的分子靶向药物、免疫治疗均无明显效果。基于上述原因，目前胰腺癌的治疗困境重重。您能就如何突破困境谈一谈您的观点吗？

　　Dr Lou: Pancreatic cancer worldwide still remains one of the most challenging cancers to treat unfortunately. There are some unique properties and some that are very similar to other cancers. It is considered a very heterogeneous disease in many ways， but firstly， in terms of the mix of malignant cells and the stroma. The stroma is compromised of a very diverse set of cells which include immune infiltration cells like neutrophils and macrophages. There is the opportunity for angiogenesis， and vascular endothelial growth factor helps promote that. There are also pancreatic stellate cells which form the base of the desmoplastic reaction. This causes a very dense tumor stroma matrix that is very difficult to penetrate and one of the key difficulties in allowing standard chemotherapy drugs to penetrate the tumor and work effectively. A prime example I can give of that is the HALO trial here in the United States involving a drug called pegylated hyaluronidase. The aim of this enzyme is to break down the barriers that exist around pancreatic tumors. The barrier includes hyaluronic acid which at the cellular level is a proteoglycan. This forms a barrier， almost like a wall around the pancreas tumor. For years we have been trying to overcome this problem and this enzyme helps to break down the barrier and allow better penetration of chemotherapy. Dr Sunil Hingorani from the Fred Hutchinson Cancer Research Center provided some very exciting data here at the meeting， still in its early stages of early phase II trial data based on phase I studies examining the safety of this drug in combination with standard chemotherapy. So far， progression-free survival is over double that of the standard chemotherapy combination. We don’t yet know the overall survival data but it looks extremely promising. As with anything， randomized clinical trials are required and what we are trying to understand at the laboratory level is what molecular targets can be targeted with effective therapy. Here at the ASCO Annual Meeting， we are hearing a lot about immunotherapies. The barriers around pancreatic tumors are still not allowing immunotherapies to work effectively at present but if we have a way to break down the barriers as with hyaluronidase， it might allow the immune system to attack the tumor in conjunction with standard chemotherapy.

　　Dr Lou: 不幸的是，在世界范围内胰腺癌的治疗仍然是最具挑战性的癌症之一。胰腺癌具有一些与其他癌症非常类似的特性，但是它也具有一些很独特的性质。在许多方面胰腺癌被认为是一个异构性疾病，主要表现在恶性肿瘤细胞和基质细胞的混合。基质是由多种多样的细胞组成，包括免疫渗透细胞，如中性粒细胞和巨噬细胞。血管内皮生长因子促进血管新生，胰腺星状细胞也有形成促结缔组织增生反应的基础。这些都将导致一个非常密集的肿瘤间质基质，这是标准化疗药物很难穿透肿瘤和有效杀死肿瘤细胞的一个关键困难所在。我想说的一个典型例子就是美国一个叫做HALO的临床试验，这是关于一种名为聚乙二醇透明质酸酶的药物研究。这种酶的目的是打破存在在胰腺肿瘤周围的屏障。在细胞水平上包括透明质酸的障碍是一种蛋白多糖。蛋白多糖形成了一个屏障，在胰腺肿瘤几乎像一堵墙。多年来我们一直试图解决这个问题，而这种酶有助于打破肿瘤屏障，允许化疗药物更好地渗透到肿瘤内部。来自弗雷德哈钦森癌症研究中心的Sunil Hingorani博士在这次会议上提供了一些非常激动人心的数据。这些数据是研究这种药物结合标准的化疗方案的安全性，虽然它们是处于第二阶段临床试验早期的试验数据。但到目前为止，无进展的生存期已经超过标准化疗的两倍。虽然我们还不知道整个生存时间的数据，但它看起来非常有前途。与其他研究一样，随机对照临床试验是必需的，而我们试图在实验室方面理解对于有效的治疗方法中靶向分子的目标是什么。这次在ASCO年会上，我们听到了很多关于肿瘤免疫疗法的报告。目前胰腺肿瘤周围的屏障仍然阻碍着免疫疗法的有效工作，如果我们有一种像透明质酸酶的物质，能够打破屏障，那么就能将它与标准化疗相结合，通过肿瘤免疫疗法攻击肿瘤。

　　Oncology Frontier:So with all of that in mind， the development of pancreatic cancer drug research is facing some formidable challenges. What is your opinion on this?

　　《肿瘤瞭望》：鉴于以上情况，胰腺癌药物的研发正面临着更艰巨的挑战，您是如何看待这一观点？

　　Dr Lou: The theme of tumor heterogeneity is very prominent in pancreatic cancer. It is also prominent in many other different cancers， some of the most aggressive epithelial forms of malignancies. But amongst them， pancreatic cancer is one of the most heterogeneous diseases. Not only is the tumor stroma a barrier to effective treatment strategies， but also the degree of mutation. One of the prime examples is KRAS. KRAS is a GTPase that is permanently activated which means it is always on and overexpressing the proteins that signal downstream pathways. The implication of this is that there is the overproliferation of pancreatic cancer cells which makes them more invasive and at the clinical level in the patient， we see on CT scans that they grow and become unresectable. We know that no more than 10-15% of all pancreatic tumors are resectable and that would be the only chance for a cure. Beyond that， these molecular signals stimulate pancreatic tumor cells to be more invasive and spread to other parts of the body as metastases. KRAS is thought to be present in 90-95% of all pancreatic cancers. But what is coming to light， particularly at this meeting， is that it is primitive to say that tumors either do have KRAS or don’t have KRAS irrespective of whether we are talking about pancreatic cancer or colorectal cancer or others because there is actually a mix. Some cells will be KRAS wild types while other cells will be KRAS-mutated. In our examination of the ratio that exists， the tumors that have more KRAS-mutated cells are more aggressive and the patients live for a shorter period of time. If there is a smaller proportion， then they live longer. So there is quite a bit of difference and at the clinical level， we have not yet reached that point where we can select chemotherapy based on molecular features. With next-generation frequencing and advanced digital PCR， there are molecular tools， which we did not have five or ten years ago， that are now at our disposal. The real task for researchers around the world is to investigate this and determine how we can more specifically tailor these sequencing therapies to individual patients.

　　Dr Lou: 胰腺癌研究中非常热门的就是肿瘤异质性。在许多其他不同的癌症，尤其是一些侵袭能力非常强的上皮恶性肿瘤中，肿瘤异质性也是很突出的。但是在它们中，胰腺癌是最具有异质性的疾病之一。不仅是肿瘤基质，而且突变的程度也阻碍了有效的治疗策略。一个有名的例子是KRAS。KRAS是一个永久激活的GTP酶，这意味着它总是有活性，并在蛋白质信号下游通路中过度表达。这个的含义就是胰腺癌细胞的过度增殖使它们具有更强的侵袭性。在病人的临床水平，我们通过CT扫描可以看到它们在生长且变得不可切除。我们知道，只有不超过10-15%的胰腺癌肿瘤是可切除的，而手术是治愈胰腺癌的唯一机会。除此之外，这些分子信号刺激胰腺肿瘤细胞侵袭和扩散转移到身体的其他部位。KRAS被认为是出现在90-95%的胰腺肿瘤中。特别是在这次会议上，我们关注的不再是简单地在胰腺癌、结直肠癌或其肿瘤中有KRAS或没有KRAS突变，因为实际上它们都是突变和不突变和混合。一些细胞是KRAS突变型，还有一部分细胞是KRAS野生型。在我们存在比例的检查中，具有更多的KRAS突变型的肿瘤更具有侵袭性，病人的生存期更短。如果KRAS突变型比例较小，他们的生存期将更长。所以胰腺癌在临床层面有很大的区别，但是我们还没有达到基于分子特性选择化疗这一点。随着新一代测序和精准PCR技术的出现，通过这些5-10年前还没有的分子技术工具，我们可以应用它们给病人个体化治疗。而现在全球的研究机构的任务就是如何通过这些特殊的分子剪刀来裁剪序列从而达到个体化精确治疗。

　　Oncology Frontier: Recent existing literature has reported on the effects of diet and nutritional factors on pancreatic cancer， but studies of the interaction between pancreatic cancer genes and the environment and diet are scarce in the Chinese literature. What is your opinion on this observation?

　　《肿瘤瞭望》：近期国外已有文献报道饮食及营养因素对胰腺癌发病的影响，但中国关于胰腺癌基因与环境、饮食交互作用的研究十分匮乏。不知道在您的研究范围内有没有关注这个问题？

　　Dr Lou: What is not yet known is what the differences are between the Chinese population and Western populations， for example. But we know that one of the risk factors is smoking. Smoking will double the risk for pancreatic cancer for those who smoke cigarettes versus those that don’t. Obesity in the United States and the increased risk for diabetes is also a significant risk factor for developing pancreatic cancer. As other parts of the world adopt the so-called Western diet， there is an increased risk (particularly in Asia) for the development of pancreatic cancer. Unfortunately there are no screening tests for this type of cancer so we have to manipulate the preventable causes of pancreatic cancer to reduce the cancer risk in individuals. There are things we can’t prevent in the development of cancer but we can avoid the use of tobacco， watch our diet and exercise appropriately. There are not copious numbers of randomized controlled trial data to say how long people will live or not live. For colon cancer though， it is known that patients who exercise 4-5 times per day， walking 30-45 minutes per session will certainly have a reduced risk for the occurrence of cancer. It would not surprise me that results would be similar for pancreatic cancer. It’s really common sense that exercise will be good for you and in conjunction with good nutrition， I think these will certainly be avoidable risk factors for pancreatic cancer as well as other cancers.

　　Dr Lou: 中国人群和西方人群之间的差异是什么还不清楚。但我们知道胰腺癌的一个风险因素是吸烟。与不吸烟的人相比，吸烟将会加倍胰腺癌的风险。在美国肥胖和糖尿病也增加患胰腺癌的风险，而且它们也是很重要的危险因素。随着世界其他地区开始采用所谓的西方饮食，饮食确实增加胰腺癌的发生风险（尤其是在亚洲）。不幸的是，直到目前还没有一种为这种类型的癌症进行筛查的检查，所以我们需要掌握胰腺癌的预防因素来减少个人患癌症的风险。癌症的发生中有些因素我们无法预防，但我们可以避免使用烟草，适当注意我们的饮食和加强锻炼。没有大样本的随机对照试验的数据说人们会活多久。众所周知，如果每天运动4-5次，步行30-45分钟可以减少结肠癌的发生风险。而我毫不质疑这也适用于胰腺癌。我们知道，锻炼与良好的营养对人们的健康有益。我认为这些是胰腺癌及其他癌症可避免的危险因素。