Abstract P208: Synergistic antitumor activity of lisaftoclax (APG-2575) and alrizomadlin (APG-115) through dual targeting of BCL-2/MDM2-P53 apoptotic pathways in preclinical models of acute myeloid leukemia

Abstract

Abstract Background: In many hematologic malignancies, BCL-2 is overexpressed and is a viable therapeutic target. In relapsed or refractory acute myeloid leukemia (R/R AML), BCL-2 inhibitor venetoclax as a single agent has limited activity, thereby necessitating combination treatments, some of which are actively under clinical development. In addition, the mutation rate of TP53 is rare in AML, and the frequency of MDM2 overexpression is high, representing an opportunity for pharmacologic intervention of the MDM2-P53 apoptosis pathway. Synergistic effects of MDM2 inhibitor idasanutlin and venetoclax have been reported in preclinical models of TP53 wild-type AML (Pan et al, Cancer Cell 2017). Lisaftoclax (APG-2575) and alrizomadlin (APG-115) are novel BCL-2 and MDM2 inhibitors, respectively. They show unique pharmacological properties as well as clinical activity and tolerable safety profiles in patients with hematologic or solid malignancies (Tolcher et al, J Clin Oncol 2021:2506; Ailawadhi et al, J Clin Oncol 2021:7502). Here, we examined the effects of combined lisaftoclax and alrizomadlin in preclinical models of AML. Materials and Methods: AML cell lines and mouse xenograft models were employed. Antiproliferative activity was measured by CellTiter-Glo luminescent cell viability assay. Apoptosis was evaluated by annexin V/propidium iodide staining and flow cytometry. Meso-Scale Discovery ELISA assay and western blot analyses were used to characterize the mechanisms of the synergistic effects of this combination. In animal studies, clinically relevant doses of lisaftoclax were employed. A pulsed high-dose regimen of alrizomadlin was used to achieve best efficacy and manage on-target toxicity. Results: In TP53 wild-type AML cell lines MOLM-13, MV-4-11, and OCI-AML-3, both single-agent lisaftoclax and alrizomadlin exerted apoptogenic activity. The combination had synergistic apoptogenic and antiproliferative activity. In subcutaneous xenograft models derived from MV-4-11 and OCI-AML-3 cells, the combination substantially inhibited tumor growth relative to the impact observed with either single agent. In a systemic xenograft model derived from MOLM-13 cells, the combination significantly (P < .05) extended the life span of tumor-bearing mice by 135% to 237% compared to that of tumor-bearing mice treated with lisaftoclax or alrizomadlin alone, which resulted in extensions of 4% to 26% and 41% to 95%, respectively. Synergistic anti-leukemic activity was confirmed in a patient-derived systemic AML model. Mechanistically, the combination synergistically downregulated anti-apoptotic proteins MCL-1 and BCL-xL and primed AML cells to apoptosis induced by lisaftoclax. Conclusions: We show a significant synergy of lisaftoclax and alrizomadlin and novel mechanisms associated with the combination of these agents in preclinical models of TP53 wild-type AML. These data support investigation into the clinical outcomes of the combination treatment in patients with TP53 wild-type AML. Citation Format: Douglas D. Fang, Qiuqiong Tang, Qixin Wang, Na Li, Feng Zhou, Guoqin Zhai, Yan Yin, Dajun Yang, Yifan Zhai. Synergistic antitumor activity of lisaftoclax (APG-2575) and alrizomadlin (APG-115) through dual targeting of BCL-2/MDM2-P53 apoptotic pathways in preclinical models of acute myeloid leukemia [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P208.