Oncology (Williston Park). 2011 Nov 15;25 Suppl 2(12 0 2):56-64.
The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor (PI) bortezomib (Velcade) against relapsed and relapsed/refractory multiple myeloma. Another generation of PIs is now entering the clinical arena; this includes intravenous agents such as carfilzomib, CEP-18770, and marizomib, and oral drugs such as MLN9708 and ONX 0912. These novel agents will likely first be used for patients with disease that has either relapsed or been refractory to prior therapy (including bortezomib-based regimens) because of their ability to overcome drug resistance, or will be used in patients who are intolerant of, or are not candidates for bortezomib. Preclinical studies also suggest that PIs may act synergistically with other conventional and novel agents, or even with one another in rationally designed combination regimens. In addition, other inhibitors that selectively target only the immunoproteasome and not the constitutive proteasome, as well as agents that bind to noncatalytic proteasome subunits, are emerging as potential drug candidates. Taken together, it seems likely that we have only begun to appreciate the full potential of inhibition of the proteasome. This article extrapolates our current knowledge into an algorithm for the future use of these inhibitors against multiple myeloma.
泛素-蛋白酶体途径最初被证实是癌症治疗的一个靶点，硼酸盐蛋白酶体抑制剂（PI）硼替佐米（万珂）对复发性和难治性多发性骨髓瘤的活性证明了这一点。现在，另一代蛋白酶体抑制剂正进入临床领域；这包括静脉注射药物，如卡非佐米、CEP-18770 和 marizomib，以及口服药物，如 MLN9708 和 ONX 0912。这些新型药物可能首先用于那些对先前治疗（包括硼替佐米为基础的方案）有复发或耐药的疾病患者，因为它们能够克服耐药性，或者用于不能耐受或不适合硼替佐米的患者。临床前研究还表明，蛋白酶体抑制剂可能与其他常规和新型药物协同作用，甚至在合理设计的联合方案中相互作用。此外，其他选择性靶向免疫蛋白酶体而不是组成型蛋白酶体的抑制剂，以及与非催化蛋白酶体亚单位结合的药物，正在成为潜在的药物候选物。综上所述，似乎我们才刚刚开始充分认识到抑制蛋白酶体的全部潜力。本文将我们目前的知识外推到一种针对多发性骨髓瘤未来使用这些抑制剂的算法中。
