TRLS-10 A NOVEL GABA TRANSAMINASE INHIBITOR (OV329) IN COMBINATION WITH DOCETAXEL DELAYS METASTATIC PROGRESSION IN A PRECLINICAL MODEL OF TRIPLE-NEGATIVE BREAST CANCER

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a high propensity for metastasis to the brain, liver, and bone—sites associated with poor prognosis. Recent evidence suggests that TNBC exploit central nervous system (CNS) metabolic pathways, including the γ-aminobutyric acid (GABA) pathway, to support metastatic growth. OV329 is a novel small-molecule inhibitor of GABA transaminase (ABAT), developed to target this metabolic vulnerability. Here, we evaluated the therapeutic potential of OV329, alone and in combination with Docetaxel, in a murine intracardiac model of TNBC. Pharmacokinetic analyses demonstrated that OV329 achieves measurable CNS exposure, with sustained ABAT inhibition despite rapid systemic clearance. In vivo bioluminescent imaging (BLI) revealed that combination therapy with OV329 (2.0 mg/kg, p.o. daily) and Docetaxel (12.5 mg/kg, i.v., Q4D ×3) significantly delayed the onset of brain metastases compared to Docetaxel alone (p = 0.0234) or vehicle control (p = 0.0096). OV329 monotherapy did not significantly alter metastatic timing. Similar trends were observed in liver and bone, where combination treatment extended time to metastasis relative to monotherapies or control. Notably, the delay in liver metastasis with combination therapy was significant compared to both vehicle (p = 0.0207) and Docetaxel alone (p = 0.0033), highlighting enhanced systemic efficacy. These findings suggest that OV329, by targeting tumor metabolic adaptations, complements the cytotoxic effects of Docetaxel to impede metastatic progression across multiple organ sites. Furthermore, the sustained pharmacodynamic activity of OV329 supports its utility in CNS-targeted regimens. Collectively, this study underscores the therapeutic promise of ABAT inhibition in TNBC and provides a compelling rationale for further clinical evaluation of OV329-based combination strategies to improve outcomes in patients with high metastatic risk.