美国国立癌症研究所  王心伟教授

 

　　编者按： 与其他类型的实体瘤非常相似，肝癌是一种具有高度异质性的肿瘤，最近一项基于全基因组测序和外显子测序的研究结论也进一步印证了该观点。因此从某种意义上来讲，肝癌的这种复杂的遗传学改变决定了肝癌患者个体之间存在着巨大差异。这为肝癌患者的个体化治疗带来了巨大的挑战。这些变化不仅与难以找到有效的肝癌治疗靶标有关，而且还可导致肿瘤的多重耐药。那么，我们应该如何处理这种高异质性肿瘤？在2016年9月召开的第十届国际肝癌协会（ILCA）年会上，美国国立癌症研究所（NCI）人类肿瘤实验室副主任、肝癌组组长王心伟教授介绍了目前有关肝癌分子分型研究及相关基因信号通路研究的最新进展。会后，本刊特邀请王教授针对该问题进行了专访。现将其内容整理成文，以飨读者。

 

　　肝癌分子分型最新进展

 

　　与其他肿瘤研究进展相一致，科学家们正在致力于通过分子特征或其他的一些可能的预测指标对肝癌患者进行分层，以期进行靶向治疗。事实上，这方面的研究已经进行了超过十年，包括美国NCI王心伟教授肝癌课题组在内的诸多中心已经开始对肝细胞癌和胆管细胞癌这两类肝癌的分子学特征进行系统分析，以期通过肿瘤生物学行为特征将肝癌患者分为几种亚型，继而为肝癌的精准化治疗奠定基础。

 

　　目前，有关肝癌分子分型的标志物研究有了巨大进展。例如，最新的一项tivantinib临床研究利用了生物学标志物c-Met筛选出阳性患者进行治疗，该项研究目前仍在进行当中。而在另一项业已完成的研究中，王心伟教授研究团队与我国复旦大学附属中山医院汤钊猷院士、樊佳教授、孙惠川教授团队合作，发现一个具有特殊分子标志物的患者亚群，其microRNA26的改变使患者对于IFN-α治疗及预防复发具有良好应答。基于这项研究成果，他们已经启动了一项Ⅲ期临床试验进行大样本量的验证。

 

　　综上所述，目前已经越来越多的生物学标志物被用于肝癌患者的分子分型，通过相关的临床试验我们期待其用于指导肝癌患者的治疗策略。这也是我们将来在该领域中继续努力的方向。

 

　　肝癌转移复发机制研究

 

　　十几年来，王心伟教授研究团队与我国复旦大学附属中山医院汤钊猷院士、钦伦秀教授团队在有关肝癌转移复发机制方面有着紧密的合作。他们希望通过研究，寻找到肿瘤原发灶与转移灶之间的分子学差异，进而探寻肝癌转移复发相关分子机制，从而在根本上解决目前肝癌患者远期生存难以进一步提高的瓶颈问题。

 

　　通过十余年的深入研究，他们发现不同器官的转移灶之间各有不同，原发灶和转移灶肿瘤的分子学改变具有器官特异性的特点，例如肝癌肺转移、淋巴结转移灶以及腹腔转移灶之间具有不同的基因改变。在今年8月刚发表在Cancer Cell杂志的最新研究中，采用全基因组解析肝癌转移的特异性基因时发现，高尔基体相关蛋白（GOLM1）与肝癌肝内远处转移和患者不良预后密切相关；进一步机制研究发现，GOLM1促进肝癌转移进程是通过调控细胞内EGFR再循环途径实现的。

 

　　王教授解释说，GOLM1又名高尔基膜蛋白（GP73），与肝癌转移尤其是在肺转移密切相关的。它可以准确地调节肿瘤细胞酪氨酸激酶受体、蛋白转运，尤其是膜转运，这是肿瘤细胞逃逸转移的重要机制之一。该研究发现，GOLM1可调控多种不同类型的酪氨酸激酶受体，例如现已公认的肺癌肺转移的EGFR受体信号。此外，该基因还调控着多种肿瘤相关的受体酪氨酸信号激酶。王教授总结道：“目前已经有多种针对酪氨酸激酶受体的肝癌靶向治疗药物在临床试验环节中失败，这项研究让我们找到了一个全新的肝癌治疗靶点，有望用于肝癌的临床治疗。”

 

　　前景展望

 

　　王教授表示，他们的前期研究主要集中在“瘤间异质性”的研究，即肿瘤与肿瘤之间的差异。这只是该领域的其中一个问题，另一个问题是“瘤内异质性”的研究，即在每一个肿瘤中，肿瘤细胞之间存在不同。它可导致患者在药物反应、多药耐药等表型方面的差异问题，因此当务之急是进一步揭示肿瘤内部的协调机制。这方面单细胞基因组研究为我们带来了希望，王教授认为未来有关肿瘤细胞内在相关机制，以及肿瘤细胞之间的相互作用的研究对于肝癌的个体化治疗具有重大意义。

 

　　Interview with Dr. Wang Xin Wei

 

　　Interviewer: Professor Wang, HCC is such a difficult tumor; there’s a lot of inter and intra-tumor heterogeneity. So, much has been done with molecular classification and to stratify patients. So can you please talk about this?

 

　　Dr. Wang:Yes, so liver cancer is very similar to the other types of solid tumors. It is extremely heterogeneous-this is based on a recent study based on the whole genome sequencing project and exome sequencing. We found that liver cancers tend to be quite different in the sense that they are a very complex landscape of genetic alterations. As a result, you see that each tumor differs from each other in terms of genetics and tumor biology. On top of this, there are also tumor cells within a tumor that differ from each other. So this creates enormous challenges in terms of how you manage those patients individually, as well as, how do you actually deal with a tumor that has a continuously moving target? And those changes apparently link to not only failed identification of biomarkers that allow you to find effective driver targets, but on top of this, also, those changes lead to drug resistance. So therefore, those areas of studies are quite important for us to really understand. So today’s sessions will mainly discuss intratumor heterogeneity and intertumor heterogeneity-two elements that are quite important for addressing liver cancer management, and particularly in the new area of personalized medicine, for example, and treatment.

 

　　Interviewer: So can you please elaborate on the molecular classification of this approach?

 

　　Dr. Wang:So, those studies actually had been conducted perhaps more than ten years ago. Many of the research groups, including ours-the research group for the National Cancer Institute-have systemically started characterizing liver cancer, particularly hepatocellular carcinoma and cholangiocarcinoma, to identify how many individual patient subgroups are there with very unique tumor biology that allow us to find a way to find biomarkers for each subgroup. And then you could actually now find a strategy to enrich those subgroups for particular treatments. So, those studies began about ten years ago, and we are now into an area where we think we can make the next wave. In a way, very similar to breast cancer research, for example, we can now subclassify patients into different subgroups with very homogenous populations. And with druggable targets, perhaps we can design studies for clinical trials for those approaches. Now, one of the recent studies on biomarker rich therapy trials is a c-Met trial, tivantinib, as one of the examples in which we don’t know the results yet. In another study that we have done, with Professor Tang Zhao You in China, we identify a subpopulation of patients with particular biomarker changes. This is in working together with Professor Fan Jia and Professor Sun Hui Chuan from the Liver Cancer Institute of Shanghai, Fudan University. And now we have launched a Phase III clinical trial to enrich patients, particularly with a change of this particular microRNA called microRNA-26. Patients with changes in microRNA tend to respond quite well with this particular treatment-in this case the interferon alpha treatment-to prevent patient relapse. So this is at least two examples that we could use biomarkers to enrich patients, to perhaps improve patient response to a particular treatment. And that would be a continual effort for the future for this very deadly disease.

 

　　Interviewer:So what would be the problems and shortagesin using molecular classification to address liver cancer?

 

　　Dr.Wang:Yes, so in our early study, as I mentioned, we had been very much focused on study as an intertumor heterogeneity-how each tumor differs from each other. Now, we recognize this as one of the area of issues. The second area of issue is intratumor heterogeneity, meaning that within each tumor, tumor cells behave differently. And this is becoming more problematic in terms of drug response, drug resistance, for example, phenotypically.So, the idea is to allow us to find a way to understand the tumor community. How does the tumor community work together collectively? So today’s topic will be focusing, mainly, on the single cell genome. Hopefully, we will understand what is the tumor cell community, how does each tumor cell behave with each other.

 

　　Interviewer: So Professor Wang,can you please introduce your article about “GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis” published on Cancer Cell?

 

　　Dr. Wang: Thank you for the question.This is a gene called GOLM1, and it isalso known as GOLPH73. This is actually one of the research questions we started more than ten years ago when we first began to collaborate with Professor Qin Lun Xiu from Fudan University, together with Professor Tang Zhao You. We asked a very simple question: so what is the difference between a primary tumor compared with a metastasis, whether the differences can be druggable and can really help us to find a way to eliminate metastasis, which is the main form that kills patients.  So, through these ten years of studies, now we’ve learned that metastases tend to work differently with different organs, and this particular study’s extension of previous work, showing that the molecular change in the primary tumor and molecular change in the metastasis tend to be organ specific, such as metastasis of the lung, metastasis of the lymph nodes, metastasis of the abdominal-all tend to have different sets of genes. This particular gene is a gene responsible for metastasis, predominantly, of the lung. So, from this initial study, we picked up the genes among those with many of the molecular changes linked to lung metastasis. This was one of the first genes that were characterized extensively. We found this rather unique. This is one of the genes that link, as a major link, to metastasis. But all throughout the study, we found that this particular gene can actually help to regulate the receptor tyrosine kinase, Protein trafficking, in particular the membrane trafficking.  This is actually one of the very important mechanisms for how a tumor cell escapes regulation that leads to a metastasis. So we think that in this particular study that this one gene regulates multiple different types of receptor tyrosine kinase, including, for example, EGFR receptor signaling-which now we know is very important for lung metastasis in lung cancer-and many, many other receptor tyrosine signaling kinases that are known to be involved in many types of cancer. There are many different kinds of drugs now being developed as inhibitors to target those receptor tyrosine kinases, so we think this particular study allows us to find a way to quickly identify a particular type of drug that may help to translate to clinical management of this type of tumor with metastasis of the lung.