Abstract 1924: Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors

Abstract

Abstract TNF-related apoptosis-inducing ligand (TRAIL) receptor (DR4 or DR5) agonists are promising agents for cancer therapy because they induce apoptosis selectively in cancer cells. However, their clinical effect is hampered by either primary or acquired resistance in cancer cells. Second mitochondria-derived activator of caspase (Smac) mimetics that antagonize the IAPs potently sensitize cancer cells to TRAIL-induced apoptosis in a caspase-8-dependent manner. We evaluated antitumor effects of small-molecule IAP antagonist APG-1387combined with an agonist mouse mAb directed against TRAIL death receptor type 5 (DR5) termed CTB-006 in the preclinical setting. Both agents are in phase I/II clinical development for patients with solid tumors. In vitro the combination treatment showed synergy in a dose-dependent manner across various cancer cell lines, as evidenced by synergistic antiproliferative activity and enhanced induction of caspase-3 cleavage. Potential synergistic in vivo antitumor activity of the combination was then assessed in human triple negative breast cancer (TNBC) xenograft models in mice. Specifically, in MDA-MB-231 and 2LMP TNBC xenograft models, either APG-1387 or CTB-006 single agent exhibited limited antitumor activity, with T/C (%) values of >35% (T, tumor volume in the treatment group; C, tumor volume in the vehicle control group). Only one tumor showed partial regression (PR) by DR5 treatment. Addition of APG-1387 potentiated this effect, with the combination treatment leading to T/C values of 3% to 15%, and complete regression, PR, or stable disease in all treated tumors. In summary, our results suggest great potential of combination therapy with APG-1387 and CTB-006 for solid tumor therapy and deserves further clinical investigation. Citation Format: Qiang Li, Douglas D. Fang, Zhe Li, Dajun Yang, Fengqi Cao, Yifan Zhai. Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1924.