Efficacy of DNA polymerase inhibitors in breast cancer using breast intraductal mouse model
Swiss partners
- EPFL: Cathrin Brisken (main applicant), Georgios Sflomos
Partners in the MENA region
- American University of Beirut, Liban: Nadine Darwiche (main applicant)
Presentation of the project
Breast cancer is the most diagnosed cancer among women worldwide and remains a leading cause of cancer-related deaths. Among its different forms, triple-negative breast cancer (TNBC) is one of the most aggressive and difficult to treat. Patients with TNBC often face a higher risk of metastasis, limited treatment options, significant treatment-related side effects, and poor clinical outcomes. These challenges highlight the urgent need for more effective and targeted therapies.
Our research focuses on a promising new strategy that targets DNA polymerase alpha 1 (POLA1), a protein that plays a critical role in cancer cell growth and DNA replication. We previously discovered that the adamantyl retinoid ST1926 can inhibit POLA1 and effectively suppress the growth of breast cancer cells. Building on this finding, we developed two next-generation compounds, MIR002 and GEM144, which simultaneously target POLA1 and HDAC11, another protein involved in cancer progression. Among these compounds, GEM144 demonstrated particularly favorable drug-like and pharmacokinetic properties.
Using laboratory and animal models of human TNBC, we found that GEM144 exhibits potent anticancer activity and effectively slows tumor growth. Importantly, we also investigated whether GEM144 could enhance the effectiveness of existing chemotherapy treatments. Cisplatin, a commonly used chemotherapy drug for TNBC, is often limited by toxicity and the development of treatment resistance. Our studies showed that inhibition of POLA1 significantly increases the sensitivity of TNBC tumors to cisplatin. The combination of GEM144 and cisplatin produced superior antitumor effects while maintaining acceptable tolerability in a clinically relevant intraductal breast cancer mouse model.
These findings identify POLA1 as a promising therapeutic target and support the continued development of GEM144-based combination therapies. By improving the effectiveness of existing treatments and potentially reducing the burden of drug resistance, this approach may offer new hope for patients with TNBC, a disease for which effective targeted therapies remain urgently needed.