Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain.
Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain; Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain.
Gynecol Oncol. 2019 May;153(2):425-435. doi: 10.1016/j.ygyno.2019.03.002. Epub 2019 Mar 7.
The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway.
We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial.
ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment.
ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.
PI3K/AKT/mTOR 通路在子宫内膜癌（EC）中经常过度激活。我们评估了 ABLT0812 的疗效，ABTL0812 是一种新型的首创分子，具有抑制该通路的独特作用机制。
我们研究了 ABLT0812 对广泛的子宫内膜样和非子宫内膜样细胞系、诱导型 PTEN 敲除鼠模型以及两种 EC 患者来源异种移植鼠模型中的增殖、细胞死亡和细胞内信号通路调节的影响。然后，在 1b/2a 期临床试验中，评估了 TRIB3 表达作为潜在的 ABLT0812 药效学生物标志物。
ABLT0812 诱导 TRIB3 表达上调，导致 PI3K/AKT/mTOR 轴抑制和自噬细胞死亡诱导在 EC 细胞中，但不在健康子宫内膜细胞中。ABLT0812 治疗还损害了 PTEN 敲除细胞从增生到癌症的进展。ABLT0812 在体内显示出治疗效果。ABLT0812 增加了 8 名 EC 患者全血样本中的 TRIB3 mRNA 水平，表明 TRIB3 mRNA 可作为监测 ABLT0812 治疗的药效学生物标志物。
ABLT0812 通过诱导 EC 患者，包括预后较差的患者的 TRIB3 表达和自噬，可能代表一种新型且有效的治疗剂。
