Subramaniam Bavani, Roy Debasish, Woldegerima Ayda, Chong Wai Chin, Przystal Justyna M, Zhang Jie, Laternser Sandra, Kritzer Bettina, Rangnath Suraj, Knowles Truman, Yadavilli Sridevi, Packer Roger, Mueller Sabine, Nazarian Javad
Brain Tumor Institute, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
NPJ Precis Oncol. 2025 Jul 1;9(1):209. doi: 10.1038/s41698-025-01006-4.
H3K27M diffuse midline gliomas (DMG) are characterized by p53 mutations and hypomethylation of MGMT, a DNA-repair enzyme, leading to resistance towards chemotherapeutic agents such as temozolomide (TMZ). As an alternative, we investigated the efficacy of a functionally different DNA-damaging agent, Val-083, on our DMG models. Val-083 is a blood-brain barrier penetrant DNA targeting agent that induces DNA N7-guanine interstrand crosslinks, which is unrepairable by MGMT. As Val-083 also triggers S/G2 phase cell cycle arrest for DNA repair, we evaluated its combined efficacy with Wee1 inhibitor, AZD1775. AZD1775 functions by inhibiting Wee1, at G2/M checkpoint to prevent phosphorylation of CDK1 and propel cells into the M phase. This subsequently overrides cell cycle arrest and drives cells with DNA damage into premature mitosis and apoptosis. Our results showed that Val-083 and AZD1775 work additively on a range of p53 mutant and p53 wildtype DMG models to inhibit cell growth, induce DNA damage and alter cell cycle. In addition, the combination drugs led to significant increase in the number of cells undergoing apoptosis, and a decrease in the migration and invasion activity of the cells. In vivo, the combination of both drugs led to significant reduction in tumor growth in zebrafish xenograft models and prolongation of survival in mice xenograft models. Our findings indicate that Val-083 and AZD1775 in combination demonstrate promising efficacy in DMGs, providing a clinical rationale for positioning these arms in future therapies.
H3K27M弥漫性中线胶质瘤（DMG）的特征是p53突变以及DNA修复酶O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）低甲基化，从而导致对替莫唑胺（TMZ）等化疗药物产生耐药性。作为替代方案，我们研究了一种功能不同的DNA损伤剂Val-083对我们的DMG模型的疗效。Val-083是一种可穿透血脑屏障的DNA靶向剂，可诱导DNA N7-鸟嘌呤链间交联，而MGMT无法修复这种交联。由于Val-083还会触发S/G2期细胞周期停滞以进行DNA修复，我们评估了它与Wee1抑制剂AZD1775联合使用的疗效。AZD1775通过在G2/M检查点抑制Wee1来发挥作用，以防止细胞周期蛋白依赖性激酶1（CDK1）磷酸化并促使细胞进入M期。这随后会解除细胞周期停滞，并驱使有DNA损伤的细胞进入早熟有丝分裂和凋亡。我们的结果表明，Val-083和AZD1775在一系列p53突变型和p53野生型DMG模型上具有相加作用，可抑制细胞生长、诱导DNA损伤并改变细胞周期。此外，联合用药导致凋亡细胞数量显著增加，细胞的迁移和侵袭活性降低。在体内，两种药物的联合使用导致斑马鱼异种移植模型中的肿瘤生长显著减少，以及小鼠异种移植模型中的生存期延长。我们的研究结果表明，Val-083和AZD1775联合使用在DMG中显示出有前景的疗效，为在未来治疗中应用这些药物提供了临床依据。
