Abstract A055: Addressing disparate outcomes in triple negative breast cancer: Targeting metabolic and cell-cycle vulnerabilities with novel biguanide-mediated combination therapy
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Despite constituting 12.7% of breast cancer (BC) cases, TNBC comprises 40% of BC mortalities with a three-fold increase in early recurrence, 50% metastasis rate over the disease course, and a dismal 15% stage IV survival rate. Premenopausal women of African ancestry (AA) are twice as likely to be diagnosed with TNBC and 40% more likely to die from TNBC than women of European ancestry (EA). The disproportionate burden on young AA women is compounded by socioeconomic factors including heightened poverty rates, comorbidities (obesity, diabetes), and reduced access to preventative healthcare. Nonetheless, targeting ancestry-specific dysregulation of oncogenic pathways is essential to combat disparities in TNBC mortality. In RNA sequencing of patient-derived xenografts (PDXs) from two Ghanaian women, genes linked to apoptosis and hypoxia were significantly upregulated (p<0.01) along with downregulation of E2F targets (p<0.001). Increasing evidence implicates metabolic dysregulation in TNBC progression and resistance, particularly hyperinsulinemia, oxidative phosphorylation (OXPHOS) dependence, and PI3K/AKT/mTOR activation. We have developed a potent novel biguanide based on the structure of metformin, termed JD006, which significantly inhibits TNBC growth in vitro and in vivo in a dose-dependent manner (p<0.01). In TNBC cell lines representing AA and EA patients, JD006 exhibits multi-pronged antiproliferative activity by inducing AMPK phosphorylation, inhibiting downstream mTORC1 signaling at S6 and 4E-BP1, and inducing apoptosis by reducing levels of Bcl-2, Bcl-xL, and Bax. Seahorse assays reveal inhibition of OXPHOS and ATP synthase with a compensatory increase in glycolysis. In syngeneic BALB/c mice, JD006 inhibited tumor growth (p<0.001) and reduced lung metastasis (p<0.05). Transcriptome analysis revealed reduced expression of OXPHOS genes in the lungs of treated mice and minimal alteration of blood glucose or lactate levels. Furthermore, JD006 decreases cyclin D1 expression, thus intersecting with cyclin-dependent kinase 4 and 6 (CDK4/6)-mediated control of E2F targets and the G1-S cell cycle transition. When combined with CDK4/6 inhibitors, JD006 overcomes acquired resistance through the PI3K/AKT/mTOR signaling cascade to produce synergistic antiproliferative effects and enhanced Rb suppression in vitro. In vivo, combination therapy significantly reduced tumor growth relative to single-agent treatment in nude mice growing orthotopic AA PDXs (p<0.01). TNBC represents a highly lethal race disparity in BC outcomes, necessitating combination therapies to target its unique metabolic profile. These findings support a therapeutic paradigm in which simultaneous disruption of mitochondrial bioenergetics, cyclin D1–CDK4/6–Rb signaling, and apoptosis promotion exploit a key metabolic–cell cycle dependency in TNBC while overcoming acquired resistance. Julie Liu, Mario Morales Martinez, Eduardo Mauricio Gonzalez, Michael Jung, Gang Deng, Hyunsoo Kim, Nalo Hamilton, Linsey Stiles, Richard J. Pietras, Diana Marquez-Garban. Addressing disparate outcomes in triple negative breast cancer: Targeting metabolic and cell-cycle vulnerabilities with novel biguanide-mediated combination therapy [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr A055.