Halatsch Marc-Eric, Dwucet Annika, Schmidt Carl Julius, Mühlnickel Julius, Heiland Tim, Zeiler Katharina, Siegelin Markus D, Kast Richard Eric, Karpel-Massler Georg
Department of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, Germany.
Department of Neurological Surgery, Cantonal Hospital of Winterthur, 8401 Winterthur, Switzerland.
Pharmaceuticals (Basel). 2021 Nov 29;14(12):1241. doi: 10.3390/ph14121241.
Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1-2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide.
In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort.
CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells' migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels.
CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).
胶质母细胞瘤是成人中最常见的原发性脑肿瘤。尽管技术不断进步，但患有这种疾病的患者通常在诊断后1至2年内死亡。在寻找新型治疗方法的过程中，药物重新利用已成为传统药物开发流程的一种替代方案，有可能促进和加速从药物发现到临床应用的转变。在一项药物重新利用的工作中，最初的CUSP9及其衍生物CUSP9*和CUSP9v3是作为九种非肿瘤药物与节拍性低剂量替莫唑胺的组合而开发的。
在这项工作中，我们在不同的已建立、原代培养和干细胞样胶质母细胞瘤模型中对CUSP9v3进行了临床前测试。此外，八名经过大量预处理的复发性胶质母细胞瘤患者在最后的努力中基于同情用药接受了CUSP9v3治疗方案。
CUSP9v3在所有测试的胶质母细胞瘤模型中都具有显著的抗增殖和促凋亡作用。此外，细胞的迁移能力和形成肿瘤球的能力大幅降低。在体外，用替莫唑胺进行额外治疗并没有显著增强CUSP9v3的抗肿瘤活性。CUSP9v3耐受性良好，最常见的3级或4级不良事件是肝酶水平升高。
CUSP9v3在体外显示出强大的抗增殖和抗迁移活性，并且似乎对患者应用是安全的。这些数据促使在Ib/IIa期临床试验（NCT02770378）中对CUSP9v3进行进一步研究。
