Abstract LB191: The natural compound KH617 targets pediatric and adult high-grade gliomas

Abstract Background: Pediatric and adult high-grade gliomas (HGGs) are highly aggressive brain tumors characterized by poor clinical outcomes due to intrinsic chemotherapy resistance and challenges in drug delivery. Effective therapeutic options remain limited, necessitating the development of novel agents. Methods and Results: The efficacy of KH617 (β-elemene, β-ELE), a natural compound, was evaluated through preclinical and clinical investigations. Preclinical Results: KH617 demonstrated potent cytotoxic effects across 29 brain cancer cell cultures, including primary and secondary glioblastoma cells, temozolomide (TMZ)-resistant sublines, pediatric diffuse intrinsic pontine glioma (DIPG) cultures, and mouse glioma lines. These effects were independent of molecular characteristics, including MGMT status, stemness, and metastatic potential, indicating a distinct mechanism from TMZ. In orthotopic xenograft models: Clinical Results: KH617’s clinical translation has progressed through investigational new drug (IND) approval by the FDA on July 28, 2022, and National Medical Products Administration (NMPA) clinical trial notification on September 22, 2022. A Phase I open-label trial was initiated to determine the recommended Phase II dose (RP2D) in patients with recurrent GBM (rGBM) and advanced solid tumors.To date, over 20 patients have been enrolled in the dose-escalation stage, reaching the maximum dose level without dose-limiting toxicities. Safety outcomes have exceeded expectations, and tumor volume reductions demonstrated a dose-dependent response, supporting the preclinical findings. Conclusions: Integrating robust preclinical data and encouraging early clinical outcomes, KH617 emerges as a promising therapeutic candidate for pediatric and adult HGGs, addressing critical unmet needs in neuro-oncology. Citation Format: Manqian Zhao, Liang Ye, Litao Liu, Xiao Ke, Jian Teng, Bakhos A. Tannous. The natural compound KH617 targets pediatric and adult high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB191.