Abstract 3341: Targeting CXCR4 via the small molecule inhibitor NMX1 as a therapeutic strategy to treat high-risk malignancies
Authors: Patrick Sipila, Son Tran, Chunfen Zhang, Laura G. Corral, Kyle W. Chan, Cathy A. Swindlehurst, Aru Narendran
Journal: Cancer Research (2024)

Abstract Introduction: Cytokines are secreted by various cells of the immune system, endothelium, and stroma that play a critical role in cell survival. The activation of C-X-C chemokine receptor type 4 (CXCR4) by its ligand SDF-1 leads to signaling by the AKT and mTOR pathways. CXCR4 is highly expressed in several types of cancer and contributes to tumor growth, metastasis, and resistance to therapy. Interleukin 11 (IL-11) is a cytokine that often drives disease progression, as well as contributing to tumor immune evasion. NMX1 (NovoMedix) is a novel oral small molecule that inhibits mTOR signaling, CXCR4 expression, IL-11 secretion, and activates AMPK. In animal models of breast cancer, NMX1 effectively prevented tumor growth and metastasis, while also protecting from doxorubicin-induced cardiotoxicity. In this study, we investigated the anticancer activity of NMX1 in preclinical models of high-risk pediatric and adult malignancies. Methods: Cell viability assays using alamar blue were performed in a panel of pediatric and adult cancer cells, including leukemia, brain, breast, lung, neuroblastoma, and sarcoma. Cells were treated with increasing concentrations of NMX1 ranging from 250 nM to 16 µM for 96 hours, followed by determination of half maximal inhibitory concentrations (IC50). To validate target modulation, the level of IL-11 and CXCR4 was determined by ELISA and immunoblot, respectively. Protein kinase activity was assessed by phosphorylation levels. Induction of apoptosis was confirmed by caspase-mediated PARP cleavage. To identify effective drug combinations, NMX1-treated cells were screened with a comprehensive drug library. Synergy was evaluated in the top candidates by dose-response matrices and SynergyFinder. Safety and tolerability was tested in animal models. Results: NMX1 treatment induced cytotoxicity at micromolar concentrations in diverse types of cancer, with IC50 values ranging from 0.2-8.7 µM and 0.4-4.4 µM for leukemia and solid tumor cells, respectively. NMX1 induced cancer cell death by PARP cleavage and apoptosis. Mechanistically, CXCR4 expression, mTOR signaling, and IL-11 secretion were decreased upon treatment with NMX1, validating effective target modulation. The drug combination screen identified several candidates in a tumor type-dependent manner. Synergistic effects were observed using NMX1 combined with clinically relevant concentrations of rucaparib, linsitinib, and crizotinib, which target PARP, IGFR, and c-MET, respectively. Conclusions: Our study shows antitumor activity by NMX1 through inhibition of CXCR4, IL-11, and mTOR signaling, providing an effective therapeutic strategy for high-risk and refractory malignancies. Preclinical data on feasible drug combinations and biological correlates of activity support development of early phase clinical studies involving NMX1. Citation Format: Patrick Sipila, Son Tran, Chunfen Zhang, Laura G. Corral, Kyle W. Chan, Cathy A. Swindlehurst, Aru Narendran. Targeting CXCR4 via the small molecule inhibitor NMX1 as a therapeutic strategy to treat high-risk malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3341.