Abstract PS3-12-08: Rac/cdc42 inhibitor mbq-167 modulates the breast tumor immune microenvironment

Abstract A uniform therapeutic approach for metastatic breast cancer has been challenging, especially for triple negative breast cancer (TNBC), due to the inherent heterogeneity and lack of targetable receptors. Therefore, we developed MBQ-167, as a specific inhibitor of the homologous Rho GTPases Rac/Cdc42 and demonstrated its efficacy in pre-clinical mouse models of HER2 (3+) and TNBC. MBQ-167 is currently in Phase 1 clinical trials in advanced BC patients, and so far, have not shown any adverse events, and is bioavailable at acceptable levels. Emerging data show the relevance of the tumor microenvironment (TME) to malignant cancer progression, where immunosuppressive immune cells such as macrophages, neutrophils, and Myeloid-Derived Suppressor Cells (MDSCs) are recruited to the TME to promote tumor cell invasion. Moreover, in the TME, cancer cells may hijack the infiltrating cytotoxic T cells by expressing programmed death ligand (PD-L1), which binds the PD-1 receptor on T cells to induce T cell death. The crosstalk signaling between the immune cells in the TME to instigate metastatic cancer cell migration into the circulatory system is regulated by Rac and Cdc42. Therefore, we investigated the effect of MBQ-167 on the TME and inflammatory responses to further demonstrate its potential as a TNBC therapeutic. By immunophenotyping cells from spleens and tumors following administration of vehicle or MBQ-167 to Balb/C mice bearing 4T-1 TNBC tumors, we found that MBQ-167 treatment significantly reduced macrophages (particularly M2 macrophages), MDSCs, and increased CD8+ T cells. Parallel to a decrease in lung metastases, MBQ-167 increased the CD8+ Granzyme B+ regulatory T cell ratio. Of the cytokines released into the TME to activate inflammatory and immunosuppressive immune cells, we found Interleukin-6 (IL-6) to be significantly decreased in mouse plasma following MBQ-167 treatment. As published by us, gene set enrichment analysis of the transcriptomic data from 4T-1 tumors in Balb/c mice treated with vehicle or MBQ167 demonstrated a statistically significant ∼2-fold downregulation in the inflammatory mediators chitinase-3-like protein 1 (CHI3L1) and S100A9 that have also been associated with breast cancer metastasis. Therefore, ELISAs were performed following vehicle, or MBQ-167 using conditioned media from TNBC cells and macrophages in tissue culture, as well as serum from Balb/C mice with 4T-1 TNBC tumors. Results show that MBQ-167 treatment significantly reduced CHI3L1 and S100A8/A9 levels from HER2+ breast cancer cells, macrophages, and serum from Balb/C mice bearing 4T-1 TNBC. In addition to creating a favorable immune environment for inhibition of tumor growth and metastasis, MBQ-167 treatment also increased PDL1 levels in MDSCs and macrophages from spleens and tumors of mice with TNBC tumors following MBQ-167 treatment. Therefore, we tested the effect of MBQ-167 individually (50mg/kg 5X a week for 4 weeks) or in combination with anti-PD1 or anti-PDL1 (10mg/kg every 3 days for 2 weeks) in the 4T-1/Balb/C mouse model. Data show that MBQ-167 administration resulted in 80% reduction in tumor growth with no toxic effects. MBQ-167 was more effective than either anti-PD1 or anti-PDL1 in single or combined therapy in this TNBC mouse model. In conclusion, the Rac/Cdc42 inhibitor MBQ-167 targets metastatic BC cells and immunosuppressive inflammatory cells in the BC TME and is a viable TNBC therapeutic. Funded by DoD/BCRP HT94252310166, BC220526 and HT94252410094, BC230070. Citation Format: A. Torres-Sanchez, A. Cruz-Collazo, N. Grafals, S. Dorta-Estremera, S. Dharmawardhane. Rac/cdc42 inhibitor mbq-167 modulates the breast tumor immune microenvironment abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-08.