Abstract 4153: Biomarker-driven polyamine pathway targeting as a treatment approach for TNBC

Abstract Triple negative breast cancer accounts for about 15% of all breast cancer diagnoses and represents the most aggressive breast cancer subtype. This study aims to use a polyamine biomarker-driven approach to treat TNBC. Polyamines are small cationic molecules important for cancer cell growth and spermidine/spermine N1-acetlytransferase (SAT1) is the rate-limiting catabolic enzyme in the pathway. Our previous work demonstrated that doxorubicin induces SAT1 expression in moderate-SAT1 expressing TNBC models. We hypothesize that the effectiveness of using an SAT1 agonist to treat TNBC is dependent on baseline SAT1 expression and function. TNBC cell lines and patient-derived xenografts with low, moderate, and high baseline expression levels of SAT1 were used to evaluate the hypothesis. Cell lines were treated with TNBC standard-of-care doxorubicin, the SAT1 agonist N1, N11-diethylnorspermine (DENSpm), combination DENSpm-doxorubicin, or vehicle control. Adding DENSpm to sub-therapeutic doxorubicin treatments further decreased cell viability in moderate and high baseline SAT1 expressing cells (p<0.05). DENSpm depleted spermidine in moderate-SAT1 expressing TNBC-PDX ex vivo tumours slices, which was further depleted by combining with doxorubicin. In vivo, the addition of DENSpm to doxorubicin treatment further attenuated tumour growth in moderate-SAT1 expression TNBC-PDX, which corresponded to an increase in urine diacetylspermine as an indicator of treatment effectiveness. In conclusion, the results of this study suggest that combination doxorubicin and DENSpm treatment may be an effective treatment option for TNBC tumours with moderate baseline SAT1 expression, and that urine diacetylspermine production may be indicative of treatment effectiveness. Citation Format: Chloe White, Caroline Liang, Thomas Velenosi. Biomarker-driven polyamine pathway targeting as a treatment approach for TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4153.