“There are a number of new drugs that are being developed for the treatment of metastatic castration-resistant prostate cancer.”

 

Ana Aparicio教授在采访中指出，现在有很多针对转移性去势抵抗性前列腺癌（mCRPC）的新药正在研发当中。其中，有针对DNA损伤修复通路，这一通路的改变在mCRPC中更为常见。PARP抑制剂是其中的一种代表药物，有丝分裂检查点抑制剂在作为单药治疗以及联合治疗的研究中获得了令人欣喜的结果。

 

免疫治疗无疑是重点研究方向。Aparicio教授认为，前列腺癌免疫治疗的早期经验并没有显示出真正的前景，这很大程度上可归因于患者的选择。在Aparicio教授进行的临床试验中，一些患者对免疫治疗表现出非常显著的治疗反应。她认为，现有的免疫治疗和正在探索中的免疫治疗将成为未来治疗mCRPC的治疗手段之一。

 

此外，还有一些表观遗传调节剂，一些针对通路的特异抑制剂，如PI3K通路，这可能会是一个靶点。这些都正在研发中，相信新药不久便会面世。针对骨转移的药物，如镭-223都在研究之列。

 

Prof. Aparicio: There are a number of new drugs that are being developed for the treatment of metastatic castration-resistant prostate cancer. There is the DNA damage repair pathway. Alterations have been shown to be quite prevalent in metastatic castration-resistant prostate cancers. So the PARP inhibitors are one class of agents. There are others that are inhibitors of the mitotic checkpoint and there is a lot of excitement with those drugs both as a single agent and in combination. There are， of course， the immunotherapies. Some of the early experience with immunotherapy in prostate cancer has not been really promising， but I do believe that was， for a large part， due to patient selection. Personally， I have had patients on clinical trials show very significant responses to immunotherapy. The existing immunotherapies and the ones in development will， I think， definitely be part of our treatment armamentarium for metastatic castration-resistant prostate cancer. There are also the epigenetic modulators. There are the specific pathway inhibitors for PI3kinase， for example， which may be a target in this disease. These are being explored and new agents are coming through. There are all the bone-targeted agents， like radium-223， for example.

 

 

“Now， we have so many， how are we going to prioritize them and how are we going to put them together?”

 

这一领域出现了很多令人欣喜的结果，但不可忽视一个关键问题，也是本届ASCO年会上提出的一个议题：现在我们有这么多药物，我们应当如何选择，如何组合？据Aparicio教授介绍，大部分学者认同一个观点：如果一个药物不再有效，给予mCRPC患者联合治疗。但面对如此多种类的药物，以及相应的不同联合方案，如何应用好这些治疗迫在眉睫。

 

Prof. Aparicio: There is a lot of excitement in the field. The big question， and one of the themes at meetings is that now we have so many， how are we going to prioritize them and how are we going to put them together? Most of us now accept the notion that one drug is not going to do the job and we are going to have to combine them. But with all the different possible drugs and the possible combinations， we are really going to have to think very hard about how we are going to develop these treatments.

 

 

“So there are both the clinical features and the molecular features. They tend to be aggressive disease with poor response to hormone therapy.”

 

AVPC（aggressive variant prostate carcinoma）是一个亚型，它有着前列腺小细胞癌的一些临床特点，通常为（并不总是）雄激素受体阴性，对内分泌治疗不敏感，但对铂类为基础的化疗有良好的反应。

 

“我们已经发现，在很多情况下，通常与小细胞癌形态相关的临床特征出现在没有小细胞癌证据的患者中，这是我们最初从临床特征上对该侵袭性亚性进行定义的原因”。AVPC的临床特征主要体现在溶骨性疾病，没有内脏转移，大块原发肿瘤（小细胞癌特征），高水平的LDH或者CEA，相比于高肿瘤负荷有着低水平的PSA（如＞20处骨转移灶，但PSA<10 ng/mL），检出多处淋巴结转移的标志物（小细胞癌特征）。

 

Aparicio教授对这类肿瘤进行了分子分析，并得出一个候选分子特征，即抑癌基因联合缺失（p53、Rb和p10缺失），其中两个抑癌基因与这些侵袭性亚型肿瘤普遍相关。一项随机临床试验发现，这一分子特征可以预测铂类化疗的获益。此外，Science杂志近期发表的一篇文章显示，基因修饰鼠模型表明这些抑癌基因的缺失与雄激素治疗抵抗相关，这为我们定义AVPC特征增加了新证据。

 

因此，AVPC兼具临床特征和分子特征，倾向于侵袭性疾病，对内分泌治疗不敏感，有更短的中位生存期。

 

Prof. Aparicio: Aggressive variant prostate cancers are a subset of the disease that share clinical features with the small cell carcinomas of the prostate. It is often (but not always) androgen receptor-negative， and we know from many years that it responds poorly to hormonal therapy and responds well to platinum-based chemotherapies.

 

We have found that a lot of the time， clinical features that are usually associated with the presence of small cell cancer morphology presented in men without the evidence of small cell carcinoma morphology. That is why we initially defined the aggressive variants clinically – features such as predominantly lytic bone disease， exclusive visceral metastasis， a bulky primary tumor (a characteristic of small cell carcinomas of the prostate)， high levels of LDH or CEA， low PSA levels relative to high tumor burden (specifically >20 bone metastases with a PSA <10)， where there is small cell morphology， and where there are markers of bulky lymph node metastases.

 

We characterized those tumors molecularly and we came up with a candidate molecular signature that consists of combined tumor suppressor defects (loss of p53， Rb and p10). Two of those three is generally associated with these aggressive variant tumors. We found that signature predicts for benefit from platinum chemotherapy in men treated in a randomized clinical trial. In a recent publication in Science with a genetically engineered mouse model has shown that the loss of those tumor suppressors is associated with androgen indifference， which adds biological significance to the signature that we have shown to characterize the aggressive variants.

 

So there are both the clinical features and the molecular features. They tend to be aggressive disease with poor response to hormone therapy， and tend to have much shorter median survivals also.

 

 

“We have level 2 evidence that adding platinum to cabazitaxel or docetaxel will improve outcomes.”

 

Ana Aparicio教授指出，目前定义的临床特征可以预测铂类化疗的获益。她进行的一项II期随机临床试验显示，相比于卡巴他赛单药治疗，符合APVC临床特征的患者可以更多地从卡巴他赛联合卡铂治疗中获益，而其中同时具备分子特征的患者获益更多。“如果你在诊所看到一位患者有我提到的这些临床特征，或者如果你能够得到他们的肿瘤组织并对分子标志进行测定，我们将有2级证据证明卡巴他赛或多西他赛联合铂类将改善患者预后。”

 

Prof. Aparicio: The clinical features I outlined are predictive of benefit from platinum chemotherapies. We did a phase II randomized clinical trial where men were given cabazitaxel alone or cabazitaxel plus carboplatin， and the men who had aggressive variant criteria in their clinical features benefited more from the addition of platinum to the cabazitaxel chemotherapy. The men who had the molecular features in their tumors， also benefitted more. I think that if you see a patient in the clinic who has any of the clinical criteria that I mentioned， or if you are able to get their tumor tissue and identify the signature， we have level 2 evidence that adding platinum to cabazitaxel or docetaxel will improve outcomes.

 

“What we can do to make some of the immune therapies effective against these cancers.”

 

虽然AVPC患者接受卡巴他赛或多西他赛联合铂类治疗有效率高，但持续时间短，因此事情没那么简单。“我们发现在DNA损伤修复通路中存在大量突变，我们正在探索添加那些通路的抑制剂或调节剂，以期提高化疗的效果。”因为AVPC是疾病的一个亚型，所接下来她们会开展进一步的研究，试图从疾病免疫机制中获得更多信息，转变为更有效的治疗。

 

Prof. Aparicio: The response rate is high but short-lived， so there is more to it. We have found that there are enriched alterations in DNA damaged repair pathways， so we are exploring the addition of inhibitors or modulators of those pathways with the hope of improving on the effect of chemotherapy. Then， as we study them more and because they are a subset of the disease， we will learn more about their immune profiles and what we can do to make some of the immune therapies effective against these cancers.