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 projet

Breast cancer prevalence and incidence have increased worldwide and remain the major cause of mortality and morbidity among women, including in Europe and the Middle East and North Africa (MENA) region. Breast tumors express higher DNA polymerase 1 (POLA1) levels compared to normal breast tissues. POLA1 is the initiating enzyme of DNA synthesis in mammalian cells. Dr. Nadine Darwiche (the main applicant in the MENA region) and collaborators have reported that the adamantyl retinoid ST1926 is a POLA1 inhibitor that impedes the proliferation and induces cell death of human breast cancer cells while sparing their normal counterparts. They have recently synthesized the ST1926 analogs, MIR002 and GEM144, which are dual POLA1 and histone deacetylase 11 (HDAC11). Breast tumors express higher HDAC11 levels compared to normal breast tissues.

Breast cancer patients encounter cancer recurrence and drug resistance, pressing the need for novel therapeutics. In particular, triple-negative breast cancer (TNBC) is the subtype with the least favorable outcomes due to its highly invasive nature and poor response to therapeutics. The partners aim to test for the antitumor activities and mechanisms of action of ST1926, MIR002, and GEM144 in TNBC in vitro and in vivo models. Their hypothesis is that these drugs suppress breast cancer cell and tumor growth, as breast tumors express elevated POLA1 and HDAC11 levels.

The development of adequate and orthotopic preclinical animal models provides a more suitable assessment of successful therapies. Available mouse models do not allow the development of different phases of breast tumor formation. However, breast cancer cells of any hormonal status and stage engraft intraductally in mouse teats, progress, and mimic their clinical counterparts. Dr. Cathrin Brisken (the main Swiss partner) is a leading reference in breast cancer using the orthotopic intraductal breast cancer mouse model. The partners will establish this model at the American University of Beirut in Lebanon using TNBC cell lines and patient-derived xenografts (PDXs). This latter animal model will be the first of its kind to be set in the MENA region. It will be used to treat mice with POLA1 inhibitors compared to standard therapy. In addition, the PDX model offers an opportunity to investigate patient-derived tumors and suggests specific and potentially effective treatments, therefore impacting the future of clinical research.