The first-in-class anti-cancer agent ABTL0812 is effective in preclinical models of human endometrial cancer.

e17070 Background: ABTL0812 is a first-in-class anti-cancer agent with a unique mechanism of action currently in Phase Ib/IIa clinical development for endometrial cancer and squamous NSCLC. ABTL0812 successfully culminated a Phase I clinical trial showing a high safety profile and long disease stabilizations, including 14-months stabilization in a patient with platinum-unresponsive Grade IIIC endometrial cancer with mutated PI3KCA and Akt. Methods: ABTL0812 synergy with paclitaxel and carboplatin was tested in vitro on Ishikawa cells by MTT assay. ABTL0812 in vivo anti-tumor activity was assessed in a PTEN-null inducible mouse model of endometrial adenocarcinoma development upon tamoxifen injection. In vivo synergy between ABTL0812 and paclitaxel was validated in a xenograft model orthotopically implanted with Ishikawa cells and between ABTL0812 and paclitaxel/carboplatin (P/C) in xenografts derived from a patient (PDX) with grade IIIC2 endometrial carcinoma with mutated PI3KCA. Results: ABTL0812 reduced paclitaxel and carboplatin IC50 by 1.5 and 2.1 times respectively in Ishikawa cells. Synergy with paclitaxel was found in Ishikawa orthoxenografts, showing a maximum Tumor Growth Inhibition (maxTGI) of 56,7±16,9% compared with 34.6±33.2% of paclitaxel group. ABTL0812 alone was effective reducing endometrial intraepithelial neoplasia formation in a mouse model of endometrial adenocarcinoma. Additionally, in an endometrial cancer PDX, ABTL0812 alone showed similar efficacy with reduced toxicity when compared with P/C and improved maxTGI when given in combination (ABTL0812: 45,2±17,5%; C/P*: 38,7±26,9%; ABTL0812+C/P*: 59.3±8.8%; *p=0.031). Conclusions: ABTL0812 has shown efficacy as a single agent and in combination with chemotherapy in preclinical models of endometrial cancer with mutations on PI3K/Akt pathway, which appears frequently over-activated in patients with these cancers. These results supported the application of ABTL0812 as a first line therapy in combination with chemotherapy for the Phase Ib/IIa clinical trial currently ongoing, positioning ABTL0812 as a potential therapeutic agent in the treatment of endometrial cancers bearing these genetic alterations.