TARGETING CELLULAR SIGNALING PATHWAYS IN ESTROGEN RECEPTOR POSITIVE BREAST CANCER

Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer diagnosed in women. While usually initially responsive to combinations of chemotherapy with hormonal therapies, resistance to current clinically used treatments is becoming more and more frequent. It is vital to continue to study the mechanisms of resistance to endocrine therapies and discover methods for combating this drug resistance to improve patient survival. The mixed lineage kinase (MLK) inhibitor, CEP-1347, was studied in culture and in pre-clinical models to evaluate its efficacy, alone and in combination with the clinically available selective estrogen receptor downregulator ICI 182,780, in treating endocrine sensitive and resistant ER+ breast cancers. Using cell lines models, its effects on cell viability, cell death, and cell cycle progression were analyzed, and nuclear and cellular morphology throughout mitosis were examined. Studies were expanded to animals to determine the efficacy of CEP-1347 against tumor growth in a pre-clinical setting. Tumor cell growth and death were studied, as well as the potential for tumor regrowth after the cessation of treatment. Investigation into drug efficacy were expanded into patient derived xenograft (PDX) lines and effects on cell cycle progression were analyzed.The data demonstrate that CEP-1347, especially in combination with ICI 182,780 has the potential to treat endocrine resistant disease through causing a cell cycle arrest which leads to a combination of decreasing proliferation and inducing apoptosis of tumor cells. Furthermore, inhibition of regrowth after cessation of treatment in endocrine sensitive cells suggests that perhaps if used as an earlier line therapy, CEP-1347 in combination with ICI 182,780 may slow or prevent the development of resistance.