PO.ET09.07 · 实验与分子治疗
GFH276 单药治疗及联合治疗用于 RAS 突变肿瘤的临床前评估
Preclinical evaluation of GFH276 monotherapy and combination therapy for RAS-mutant tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：RAS 突变见于 90% 的 PDAC、50% 的 CRC、30% 的 NSCLC、27% 的胆管癌、20% 的子宫体子宫内膜癌以及其他某些类型的肿瘤。KRAS G12C 是首个在临床上被攻克的 RAS 突变体，然而靶向其他同工型仍未解决。GFH276 是一种在研的分子胶 panRAS(ON) 抑制剂，目前正在一项 1 期试验（NCT07198321）中进行评估，此前已在 RAS 突变模型中显示出强效活性，并展现出源于其作用机制（MOA）相较于基于 SIIP 的 KRAS 抑制剂的优越性以及相较于竞争化合物的剂量水平优势。在此，我们呈现对 GFH276 单药治疗及其与不同治疗药物合理联合的进一步临床前评估。
方法：使用携带具有不同 KRAS 突变的 CDX 肿瘤的 BALB/c 裸鼠来确定 GFH276 单药治疗或其与 Cetuximab 联合的抗肿瘤疗效。使用携带经工程改造以带有 KRAS G12C 突变的 CT-26 肿瘤的 BALB/c 小鼠来比较 GFH276 单药治疗与其与抗小鼠 PD-1 单抗联合的效果。
结果：在一系列 NSCLC、CRC 和 PDAC CDX 模型中，每日口服给药 3 mg/kg 的 GFH276 驱动了显著的抗肿瘤疗效。在一个胆管癌和一个子宫内膜肿瘤模型中，GFH276 也以剂量依赖性方式抑制了肿瘤生长。考虑到临床上 KRAS G12C 抑制剂与 EGFR 单抗之间已验证的协同作用，我们还研究了 GFH276 加 Cetuximab 的联合治疗，结果显示与 Cetuximab 共同给药显著增强了 GFH276 的疗效。还在同基因 CT26-KRAS G12C 小鼠模型中探索了 GFH276 与免疫治疗之间的协调。在该模型中，以 0.3-3 mg/kg 的 GFH276 治疗 21 天引发了显著的抗肿瘤效应，且 3 mg/kg 组的所有动物均无瘤。与抗小鼠 PD-1 抗体的联合治疗不仅与 GFH276 给药协同，还有助于在 GFH276 停药后再维持 79 天的无瘤状态。
结论：GFH276 单药治疗在携带源自最常见 RAS 突变癌症的肿瘤的小鼠模型中有效。GFH276 还与抗 EGFR 单抗和免疫治疗表现出协同效应。这些结果描绘了 GFH276 通过不同应用策略在广泛适应症中的有前景的治疗潜力。
查看英文原文 English abstract
Background: RAS mutations are found in 90% PDAC, 50% CRC, 30% NSCLC, 27% cholangiocarcinomas, 20% uterine corpus endometrial carcinomas and some other types of tumors. KRAS G12C was the first RAS mutant clinically conquered, yet targeting other isoforms remains unresolved. GFH276, an investigational molecular-glue panRAS(ON) inhibitor currently being evaluated in a Phase 1 trial (NCT07198321), has previously shown potent activity across RAS-mutant models and demonstrated MOA-derived superiority to SIIP-based KRAS inhibitors and dose-level advantage over the competitor compound. Here we present a further pre-clinical assessment of GFH276 monotherapy and its rational combination with distinct therapeutic agents.
Methods: BULB/c nude mice bearing CDX tumors harboring different KRAS mutations were used to determine the anti-tumor efficacy of GFH276 monotherapy or its combination with Cetuximab. BULB/c mice bearing CT-26 tumors engineered to harbor KRAS G12C mutation were used to compare GFH276 monotherapy with its combination with an anti-mouse PD-1 mAb.
Results: Across a serial of NSCLC, CRC and PDAC CDX models, daily oral administration of 3 mg/kg of GFH276 drove significant anti-tumor efficacy. In a cholangiocarcinoma and an endometrial tumor models, GFH276 also inhibited tumor growth in a dose-dependent manner. Considering the validated synergism between KRAS G12C inhibitors and EGFR mAbs in clinic, combination therapy of GFH276 plus Cetuximab was also investigated and the result showed that co-administration with Cetuximab enhanced the efficacy of GFH276 significantly. Coordination between GFH276 and immunotherapy was also explored in the syngeneic CT26-KRAS G12C mouse model. In this model, 21-day treatment with 0.3-3 mg/kg of GFH276 elicited significant anti-tumor effect and all animals from the 3 mg/kg group were tumor free. Co-treatment with an anti-mouse PD-1 antibody not only synergized with GFH276 dosing , but also helped maintain the tumor free status after GFH276 dosing was stopped for another 79 days.
Conclusions: GFH276 monotherapy was effective in mouse models harboring tumors originating from most common RAS-mutant cancers. GFH276 also showed synergistic effects with anti-EGFR mAb and immunotherapy. These results depict the promising therapeutic potential of GFH276 in broad indications via different application strategies.
利益披露 Disclosure
F. Yan,
Genfleet Therapeutics Employment.
J. Zhao,
Genfleet Therapeutics Employment.
J. Zhang,
Genfleet Therapeutics Employment.
S. Le,
Genfleet Therapeutics Employment.
F. Zhou,
Genfleet Therapeutics Employment.
J. Lan,
Genfleet Therapeutics Employment.
Q. Lu,
Genfleet Therapeutics Employment.