《肿瘤瞭望》：PI治疗对于MM和部分淋巴瘤患者有效，但在实体瘤中几乎没有作用，请您介绍其原因。

　　Richardson教授：PI在实体瘤中很难发挥作用，这涉及多重生物学因素。我相信PI在实体瘤中的应用也才刚刚起步，联合治疗的策略也非常重要，但需要强调一点，是否有效要归结于肿瘤的生物学特征。总所周知，MM是一种对蛋白质降解尤其敏感的肿瘤，而实体瘤却不然。因此，实体瘤的治疗可能需要创新性的治疗策略。

　　There are a number of biological reasons and the story of proteasome inhibitors in solid tumors is starting to emerge. I think a combination strategy is going to become very important， but I must stress one thing. It boils down to biology. Myeloma is a disease that is uniquely sensitive to protein degradation and solid tumors maybe less so. In that context， more innovative strategies may be needed to take advantage of the ability to degrade proteins in the solid tumors. So there is a strong biological rationale to why myeloma is a much better suited as a target in this respect， recognizing that other indications include mantle cell lymphoma and other hematological cancers.

　　《肿瘤瞭望》：请介绍一下第二代PI的优缺点

　　Richardson教授：卡非佐米代表着新一代PI，它可以不可逆转地绑定到蛋白酶体 5 β 亚基，临床前研究显示出可克服硼替佐米耐药的情况。临床上，卡非佐米非常有效，但也有另一方的担忧，它的毒性与硼替佐米不同。好的消息是，卡非佐米的神经毒性小于硼替佐米；然而，它的血管毒性更强，虽然不是很普遍，但仍然具有挑战。总体上说，第二代PI优于第一代，并且应该联合应用。对于硼替佐米耐药的难治复发性MM患者有益。

　　Ixazomib是一种更佳优越的口服性药物，主要成分为硼酸基肽，与其他药物具有协同作用。研究表明，Ixazomib对于硼替佐米治疗失败的患者仍然有效。更加重要的是，它具有良好的安全性和耐受性，神经毒性小，几乎没有心血管毒性，这是一个非常大的进步。

　　Carfilzomib represents a second-generation proteasome inhibitor， so it is irreversibly binding to the proteasome beta-5 subunit and appears to override bortezomib resistance preclinically. Clinically， it is clearly very active but there is one word of caution. It has different toxicities to bortezomib. The good news is it is less neurotoxic. The slightly more challenging aspect is that it has vascular toxicity， which is not common but can be a challenge for vulnerable patients. It is a great new addition and should be used in combination in my opinion and is definitely indicated for relapsed/refractory disease once bortezomib failure has occurred.

　　Ixazomib represents a brilliant new advance as an oral approach. It is an oral boronate peptide and when given in combination with other drugs it synergizes and provides the convenience of all oral platform while being active even after bortezomib failure. Most importantly， it is not particularly toxic at all， is well tolerated， has less neurotoxicity， no cardiac or vascular toxicity and appears to be a very important new advance.

　　《肿瘤瞭望》：有关硼替佐米耐药的机制及其解决办法

　　Richardson教授：硼替佐米耐药机制有多种原因，药物的毒性是其中一部分。另外，生物学因素也是一个重要方面，有研究表明耐药患者的多种信号通路均出现上调，这也为我们克服PI耐药留下了重要的提示。例如，组蛋白去乙酰化酶（HDAC）抑制剂即为有效策略，通过靶向疾病相关的蛋白质乙酰化及其他表观遗传学效应，即使在硼替佐米复发的情况下，我们也可能将治疗效应逆转。

　　There are a variety of reasons. Toxicity could be one issue. On the other hand， it could also be biological and there are various pathways that can be upregulated. Why this is so important is that you can use several strategies to subvert proteasome inhibitor resistance， for example， HDAC inhibition as a strategy. By targeting the Acetylation and also the epigenetic effects of disease， you can restore response even in bortezomib refractory situations.

　　专家简介

　　Paul G. Richardson，MD 美国哈佛大学医学院Dana-Farber癌症研究院Jerome Lipper多发性骨髓瘤中心主任，国际著名多发性骨髓瘤专家，领导完成多项蛋白酶体抑制剂的国际多中心临床试验，担任NEJM、Blood、JCO等杂志特约审稿人，已发表文章300余篇。