9354 Combination Of Novel Ruthenium-Based Small Molecule Bold-100 And Capecitabine Is Effective In Inhibiting Growth Of Estrogen Receptor Positive Metastatic Breast Cancer

Abstract Disclosure: E.R. Scheidemann: None. D.M. Demas: None. N. Ashai: None. A.N. Shajahan-Haq: None. The most common breast cancer subtype in both women and men is estrogen receptor alpha positive (ER+). In the adjuvant setting, ER+ tumors are initially treated with endocrine therapy that includes antiestrogens. Mechanistically, estrogen triggers a mitogenic signaling cascade through the ER, which activates the cyclin D1-cyclin-dependent kinase 4 and 6 (CDK4/6) complex to promote cell growth. ER+ tumors that progress on antiestrogens are subsequently treated with a combination of antiestrogens and CDK4/6 inhibitors (palbociclib, ribociclib or abemaciclib). However, 20% of ER+ tumors never respond to CDK4/6i due to intrinsic resistance and the tumors that initially respond will develop acquired resistance. In the absence of driver mutations, resistant tumors are treated with standard chemotherapies, including capecitabine, which interferes with DNA synthesis. However, treatment with capecitabine show meager success and accompany adverse side effects. BOLD-100 is a ruthenium-based novel small molecule drug that demonstrated antitumor activity as a monotherapy in a phase I clinical trial with a manageable safety profile at the maximum tolerated dose. BOLD-100 has recently been investigated in a multicenter global Phase 1B/2A trial (NCT04421820) of gastrointestinal cancer patients in combination with chemotherapy FOLFOX, which includes fluorouracil, the active form of capecitabine. Previously, we have shown that in breast cancer cells, treatment with BOLD-100 disrupted proteins involved in DNA repair pathway, stimulated reactive oxygen species (ROS) and induced cell death via interrupting autophagy and inducing apoptosis. In this study, we show that combination of BOLD-100 and capecitabine synergistically inhibits growth of breast cancer cells and tumors that are resistant to CDK4/6 inhibitors. Cells treated with combination of capecitabine and BOLD-100 shows increase in apoptosis and DNA damage compared with cells treated with monotherapies or control. Therefore, capecitabine and BOLD-100 is a potential novel combination therapy for breast cancer that has progressed on standard of care treatment. Presentation: 6/2/2024