Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Cell Physiol Biochem. 2020 Jul 29;54(4):707-718. doi: 10.33594/000000250.
BACKGROUND/AIMS: Despite enormous effort, anti-angiogenic drugs have not lived up to the promise of globally-enhancing anti-cancer therapies. Clinically, anti-angiogenic drugs have been used to persistently suppress vascular endothelial growth factor (VEGF) in order to "normalize" dysfunctional neo-angiogenic microvasculature and prevent recruitment of endothelial progenitors. Recently, we showed that a 1h pre-treatment with anti-angiogenic drugs prior to ultra-high single dose radiotherapy and specific chemotherapies transiently de-represses acid sphingomyelinase (ASMase), leading to enhanced cancer therapy-induced, ceramide-mediated vascular injury and tumor response. Here we formally decipher parameters of chemotherapy induction of endothelial sphingolipid signaling events and define principles for optimizing anti-angiogenic chemosensitization.
These studies examine the antimetabolite chemotherapeutic gemcitabine in soft tissue sarcoma (STS), a clinically-relevant combination.
Initial studies address the theoretic problem that anti-angiogenic drugs such as bevacizumab, an IgG with a 3-week half-life, have the potential for accumulating during the 3-week chemotherapeutic cycles currently standard-of-care for STS treatment. We show that anti-angiogenic ASMase-dependent enhancement of the response of MCA/129 fibrosarcomas in sv129/BL6 mice to gemcitabine progressively diminishes as the level of the VEGFR2 inhibitor DC101, an IgG, accumulates, suggesting a short-acting anti-angiogenic drug might be preferable in multi-cycle chemotherapeutic regimens. Further, we show lenvatinib, a VEGFR2 tyrosine kinase inhibitor with a short half-life, to be superior to DC101, enhancing gemcitabine-induced endothelial cell apoptosis and tumor response in a multi-cycle treatment schedule.
We posit that a single delivery of a short-acting anti-angiogenic agent at 1h preceding each dose of gemcitabine and other chemotherapies may be more efficacious for repeated sensitization of the ASMase pathway in multi-cycle chemotherapy regimens than current treatment strategies.
背景/目的：尽管付出了巨大努力，但抗血管生成药物并未兑现全面增强癌症治疗效果的承诺。临床上，抗血管生成药物一直用于持续抑制血管内皮生长因子（VEGF），以“正常化”功能失调的新生血管微循环并防止内皮祖细胞募集。最近，我们发现，在超高单次剂量放疗和特定化疗之前进行 1 小时的抗血管生成药物预处理会短暂去抑制酸性鞘磷脂酶（ASMase），从而导致增强的癌症治疗诱导的、神经酰胺介导的血管损伤和肿瘤反应。在这里，我们正式解析了化疗诱导内皮鞘脂信号事件的参数，并定义了优化抗血管生成化疗增敏作用的原则。
这些研究检查了软组织肉瘤（STS）中抗代谢化疗药物吉西他滨的情况，这是一种临床相关的联合用药。
最初的研究解决了这样一个理论问题，即贝伐单抗等抗血管生成药物，作为一种半衰期为 3 周的 IgG，在 STS 治疗目前标准的 3 周化疗周期中可能会积累。我们表明，抗血管生成 ASMase 依赖性增强 sv129/BL6 小鼠 MCA/129 纤维肉瘤对吉西他滨的反应随着 VEGFR2 抑制剂 DC101（一种 IgG）水平的积累而逐渐减弱，这表明在多周期化疗方案中，短期作用的抗血管生成药物可能更可取。此外，我们发现仑伐替尼，一种半衰期较短的 VEGFR2 酪氨酸激酶抑制剂，优于 DC101，在多周期治疗方案中增强了吉西他滨诱导的内皮细胞凋亡和肿瘤反应。
我们假设，在吉西他滨和其他化疗药物的每个剂量之前 1 小时单次给予短期作用的抗血管生成药物，可能比当前的治疗策略更有效地重复敏化多周期化疗方案中的 ASMase 途径。
