■胶质母细胞瘤(GB)患者的化疗治疗标准是放射治疗(RT)联合替莫唑胺(TMZ)。然而,在它推出以来的二十年里,这个所谓的Stupp协议揭示了主要的缺点,因为近一半的GBs具有内在的治疗抗病机制。其中主要是DNA修复蛋白O6-鸟嘌呤-DNA甲基转移酶(MGMT)的表达增加和DNA错配修复(MMR)中的细胞缺陷。患有这种肿瘤的患者接受的很少,如果有的话,受益于TMZ。我们正在开发一种新的分子,NEO212(与NEO100共轭的TMZ),有可能克服这些限制。
■我们使用原位植入GB细胞系或原代的小鼠模型,抗辐射人类GB干细胞,代表不同的治疗耐药机制。动物接受无或有RT的NEO212(或用于比较的TMZ)。记录总生存期,组织学研究量化了DNA损伤,凋亡,微血管密度,以及对骨髓的影响.
■在所有肿瘤模型中,在旨在模仿Stupp协议的时间表中,用NEO212代替TMZ实现了惊人的生存扩展,特别是在抗TMZ和抗RT模型。虽然NEO212表现出明显的辐射敏感性,DNA损伤,促凋亡,和肿瘤组织中的抗血管生成作用,它没有引起骨髓毒性。
■NEO212是标准Stupp方案中可能替代TMZ的候选药物。当与放射组合时,它有可能成为第一种显着延长对TMZ耐药的患者的总体生存期的化学治疗剂。
UNASSIGNED: The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors the potential to overcome these limitations.
UNASSIGNED: We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow.
UNASSIGNED: In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity.
UNASSIGNED: NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.