Department of Neurology, Brain Tumor Center and Comprehensive Cancer Center Zurich, University Hospital and University of Zurich , Zurich, Switzerland.
Department of Medicine, Princess Margaret Cancer Centre, University of Toronto , Toronto, ON, Canada.
Expert Opin Investig Drugs. 2020 Oct;29(10):1133-1141. doi: 10.1080/13543784.2020.1803827. Epub 2020 Aug 10.
Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic options are therefore urgently needed; however, there have been various drug failures in late-stage clinical development. The proteasome represents a key target for anti-cancer therapy as successfully shown in multiple myeloma and other hematologic malignancies.
This review article summarizes the preclinical and clinical development of proteasome inhibitors in the context of glioblastoma.
Early clinical trials with bortezomib ended with disappointing results, possibly because this agent does not cross the blood-brain barrier. In contrast to bortezomib and other proteasome inhibitors, marizomib is a novel drug that displays strong inhibitory properties on all enzymatic subunits of the proteasome and, most importantly, crosses the blood-brain barrier, making it a potentially very active novel agent against intrinsic brain tumors. While preclinical studies have demonstrated significant anti-glioma activity, its clinical benefit has yet to be proven. Exploiting the biological effects of proteasome inhibitors in combination with other therapeutic strategies may represent a key next step in their clinical development.
尽管包括手术、放疗和烷化剂化疗在内的多模式治疗，胶质母细胞瘤的预后仍然很差。因此迫切需要新的治疗选择；然而，在晚期临床开发中，各种药物都失败了。蛋白酶体作为抗癌治疗的一个关键靶点，已在多发性骨髓瘤和其他血液恶性肿瘤中得到了成功证实。
本文综述了蛋白酶体抑制剂在胶质母细胞瘤中的临床前和临床开发情况。
硼替佐米的早期临床试验结果令人失望，这可能是因为这种药物不能穿过血脑屏障。与硼替佐米和其他蛋白酶体抑制剂不同，马利佐米是一种新型药物，对蛋白酶体的所有酶亚单位都具有很强的抑制作用，最重要的是，它能穿过血脑屏障，使其成为一种针对内在脑肿瘤具有潜在很强活性的新型药物。虽然临床前研究已经证明了其对神经胶质瘤有显著的抑制作用，但它的临床获益尚未得到证实。利用蛋白酶体抑制剂的生物学效应与其他治疗策略相结合，可能是其临床开发的关键下一步。
