Targeting tumor hypoxia in combined therapeutic strategies in breast and ovarian cancer
Svajda Laura
Patológiai és Onkológiai Tagozat
Dr. Matolcsy András
Országos Onkológiai Intézet
2025-05-29 15:00:00
Molekuláris és experimentális onkológia
Dr. Bödör Csaba
Dr. Tóvári József, Dr. Cserepes Tamás Mihály
Dr. Székely Borbála
Dr. Tőkés Anna-Mária
Dr. Fekete Andrea
Dr. Kocsis Zsuzsa
Dr. Rácz Gergely
Tumor hypoxia is a common feature of solid tumors and it significantly contributes to tumor progression by enhancing metastasis development. The underlying processes of tumor hypoxia are driven by the hypoxia-inducible factor 1 (HIF-1). By being responsible for the transcription of numerous genes involved in tumor progression, HIF-1 is an attractive drug target. However, HIF-1 inhibitory drugs applied as monotherapies failed in clinical trials. The combination of HIF-1 inhibitors with other therapeutics increased the efficacy of the treatment regimens. In our study, we aimed to explore strategies to improve these essential therapeutics for the treatment of highly metastasizing breast and ovarian cancers. Following suitable in vitro and in vivo hypoxia model establishments, the research was driven by complex drug-drug interaction studies, molecular and functional assays, in vivo safety and efficacy studies, proteomic and database examinations. Based on the promising preclinical background, as a HIF-1 inhibitory compound, we selected acriflavine. The antiproliferative activity of the drug was proved on a panel of breast and ovarian cancer cell lines, with the highest efficacy on triple-negative breast cancer cell lines. The proteomic profiling of these cells suggests that acriflavine interferes with migration, cell proliferation, and cellular metabolism. We opted for involving complementary treatment alongside evaluating HIF-1 inhibitory therapy. Therefore, a commonly applied taxane in breast and ovarian cancer treatment, paclitaxel was used in parallel with acriflavine. Additionally, recognizing the significance of epithelial-mesenchymal transition (EMT) in metastasis formation, an EMT-targeting compound was also analyzed. We identified a synergistic drug combination of acriflavine and paclitaxel that significantly suppressed tumor growth and metastasis formation. Enhancing this dual therapy with the EMT-inhibitory agent rolipram further strengthened its anti-metastatic effects. Based on the promising results of combining HIF-1 inhibitors with other therapies we were encouraged to evaluate the rationale behind combining ICIs and HIF-1 inhibitors. Our findings provide a clinical rationale for the concurrent use of HIF-1 inhibitors and immune checkpoint inhibitors in breast cancer treatment. These novel therapeutic strategies offer innovative approaches to tackle highly metastasizing breast and ovarian cancers.
