天然化合物KH617通过调控MGMT逆转胶质母细胞瘤对烷化剂的耐药性

Glioblastoma (GBM) represents the most prevalent and aggressively malignant glioma, with a dismal 5-year survival rate of only 6%. Alkylating agents, exemplified by temozolomide (TMZ), remain the standard of care for GBM; however, their efficacy is heavily influenced by O6-methylguanine-DNA methyltransferase (MGMT) expression. Patients with high MGMT expression exhibit limited benefit from first-line treatment, and MGMT expression tends to increase with TMZ exposure, ultimately leading to resistance. To address this critical unmet need, we have pioneered the development of KH617, a first-in-class anti-GBM candidate formulated as a lyophilized human serum albumin nanolate - a novel delivery system for an essential oil-based natural product and currently undergoing Phase II clinical trials (NCT07138001). Here, we report KH617's regulatory effects on MGMT and its potential to reverse TMZ resistance. In vitro studies employing Western blot analysis revealed an upregulation of MGMT expression in T98G human GBM cells following TMZ treatment. Conversely, KH617 treatment resulted in a significant reduction in MGMT expression that was both dose- and time-dependent. Notably, MGMT expression levels did not correlate with the IC50 value of KH617 against GBM cells. In a U87-TMZ resistant orthotopic xenograft model, we observed preliminary evidence of synergistic efficacy with the combination of injectable KH617 and TMZ: the tumor growth inhibition rate in the KH617+TMZ combination group was significantly enhanced compared to the TMZ monotherapy group (76.07% vs 29.34%, p<0.05). Regarding safety, The tunable carrier system facilitating intracellular delivery of injectable KH617 demonstrates targeted brain penetration and a peak brain-to-plasma ratio (BPR) of up to 38.67. This targeted delivery approach resulted in markedly improved tissue distribution profiles and pharmacokinetic properties, while simultaneously reducing the risk of hematological toxicity associated with endogenous MGMT-mediated chemotherapeutic sensitivity in hematopoietic cells. Current evidence suggests comparable safety profiles between the KH617 combination and TMZ monotherapy regimens. Following promising preclinical results and Phase I data showing durable benefit in some patients, a randomized, controlled, open-label, multi-center Phase II clinical study is assessing the efficacy and safety of injectable KH617 in combination with TMZ versus investigator's choice therapy (TPC) or KH617 monotherapy for recurrent GBM, and demonstrates encouraging early efficacy data. KH617, a synthetic biology empowered novel anti-GBM agent, offers a potential new treatment option for patients with TMZ resistance.