Department of NeuroOncology and NeuroOncology Program, Moffitt Cancer Center, Tampa, FL.
Department of Neurosurgery, Northwestern University School of Medicine, Chicago, IL.
Am Soc Clin Oncol Educ Book. 2022 Apr;42:1-8. doi: 10.1200/EDBK_349175.
Glioblastoma is the most common primary malignant brain neoplasm and it remains one of the most difficult-to-treat human cancers despite decades of discovery and translational and clinical research. Many advances have been made in our understanding of the genetics and epigenetics of gliomas in general; yet, there remains an urgent need to develop novel agents that will improve the survival of patients with this deadly disease. What sets glioblastoma apart from all other cancers is that it develops and spreads within an organ that renders tumor cells inaccessible to most systemically administered agents because of the presence of the blood-brain barrier. Inadequate drug penetration into the central nervous system is often cited as the most common cause of trial failure in neuro-oncology, and even so-called brain-penetrant therapeutics may not reach biologically relevant concentrations in tumor cells. Evaluation of the pharmacokinetics and pharmacodynamics of a novel therapy is a cornerstone of drug development, but few trials for glioma therapeutics have incorporated these basic elements in an organ-specific manner. Window-of-opportunity clinical trial designs can provide early insight into the biological plausibility of a novel therapeutic strategy in the clinical setting. A variety of window-of-opportunity trial designs, which take into account the limited access to treated tissue and the challenges with obtaining pretreatment control tissues, have been used for the initial development of traditional and targeted small-molecule drugs and biologic therapies, including immunotherapies and oncolytic viral therapies. Early-stage development of glioma therapeutics should include a window-of-opportunity component whenever feasible.
胶质母细胞瘤是最常见的原发性恶性脑肿瘤，尽管经过几十年的发现、转化和临床研究，它仍然是最难治疗的人类癌症之一。我们对胶质母细胞瘤的遗传学和表观遗传学有了很多的了解；然而，仍然迫切需要开发新的药物来提高这种致命疾病患者的生存率。胶质母细胞瘤与所有其他癌症不同的是，它在一个器官内发展和扩散，由于血脑屏障的存在，大多数系统性给予的药物都无法到达肿瘤细胞。药物不能充分渗透到中枢神经系统常常被认为是神经肿瘤学临床试验失败的最常见原因，即使是所谓的脑穿透性治疗药物，也可能无法在肿瘤细胞中达到生物学上相关的浓度。评估新疗法的药代动力学和药效学是药物开发的基石，但很少有胶质母细胞瘤治疗的临床试验以器官特异性的方式纳入这些基本要素。机会窗临床试验设计可以在临床环境中早期洞察新治疗策略的生物学可行性。各种机会窗试验设计，考虑到处理组织的有限机会以及获得预处理对照组织的挑战，已被用于传统和靶向小分子药物以及生物疗法（包括免疫疗法和溶瘤病毒疗法）的初始开发。只要可行，胶质母细胞瘤治疗的早期开发应包括机会窗组成部分。
