Abstract MBQ-167 is a dual Rac and Cdc42 inhibitor with significant anti-tumor growth and metastasis blocking activities in metastatic breast cancer cell and mouse models. MBQ-167 reduces both Rac and Cdc42 activation by GTP exchange and consequently, decreases phosphorylation of the common Rac and Cdc42 downstream effector p21-activated kinase (PAK). MBQ-167 is currently in Phase 1 clinical trials in advanced breast cancer patients, and so far, has shown safety and superior bioavailability up to 120 mg/kg BID (NCT06075810). Immune cell phenotyping from mouse tissue (tumor and spleen) and plasma from mice with tumors established from TNBC tumors demonstrated significant changes in myeloid cells and T lymphocytes indicating immune modulatory anticancer effects of MBQ-167 in the TME via inhibition of Rac and Cdc42. Immunohistochemistry (IHC) of breast cancer patient tissues demonstrate that Rac and Cdc42 are expressed in basal, HER2+ and (or) ER/PR+ breast cancers regardless of grade or type. However, the levels of their active downstream effector PAK, identified via IHC using a phospho (P) PAK antibody, is elevated in invasive breast cancer. Since the majority of breast cancers (∼70%) are ER+, the objective in this study is to determine the effect of MBQ-167 in ER+ breast cancer, using an ex vivo drug testing platform. ER+ breast cancer patient tissues (2 cm lesion) were collected immediately following surgical resection. Tissue slices (5 mm) were incubated in 0-1000 nM MBQ-167 for 24 h in ex vivo culture and fixed for H 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-11-12.
Collazo et al. (Tue,) studied this question.