19060 – Combination therapy for the treatment of breast cancer

Breast cancer is one of the most common forms of cancer with an estimated 270,000 new cases in the US each year. Diagnosed patients may be eligible for new molecular tests that aim to identify the origins of the disease to inform personalized treatment strategies. Luminal progenitors are thought to be the cell-of-origin in the deadliest forms, including triple-negative breast cancer, commonly seen in BRCA1-mutation carriers, and are the intended cellular target of treatment with PARP inhibitors. Yet our findings imply that luminal progenitors are fated to survive PARPi therapy and may explain the limited success achieved with PARPi monotherapy in metastatic breast cancer patients. To date, PARPi have been combined with chemotherapy (NCT03150576; NCT02163694), targeted therapy (NCT02208375; NCT01623349) and immunotherapy (NCT0359496, NCT02734004, NCT03594396, NCT03167619) in an attempt to elicit more potent anticancer effects. Building on observations by us and others on the importance of sex-hormones on mammary progenitors and tumorigenesis we have demonstrated a method for combining a SPRM (such as ulipristal acetate (UA)) with a PARP inhibitor (such as olaparib) to produce a synergistic effect, which consistently proved effective at reducing breast stem/progenitor capacity in >15 patient specimens despite vast inter-patient heterogeneity and BRCA mutation status. This technology would be valuable to companies with existing PARP inhibitors and/or next generation SPRM compounds and that are seeking to expand efficacy through combination therapies. Our methods for classifying cancer type by therapeutic susceptibility to combination treatment would also be valuable in the clinical trial setting. Bharti Ranavaya Bharti.Ranavaya@uhnresearch.ca 416-634-7536

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