Laurie E Littlepage
University of Notre Dame, USA
Title: The oncogene ZNF217 promotes breast cancer chemoresistance
Biography
Biography: Laurie E Littlepage
Abstract
Understanding the molecular mechanisms of therapeutic resistance is critical to identify novel therapeutics that overcomes metastasis, resistance, and death. We previously identified the transcription factor ZNF217 as a prognostic indicator for breast cancer patients. ZNF217 is overexpressed in breast and other cancers, and this overexpression promotes reduced survival, increased metastasis, and reduced response to therapy in patients and in our animal models. We determined if Znf217 overexpression contributed to chemotherapy resistance. We treated mice overexpressing Znf217 or vector with a combination therapy of microtubule inhibitor epothilone B, adriamycin, and cyclophosphamide (EAC). The mice overexpressing Znf217 had increased tumor volume and decreased percent survival compared to control mice. Mice overexpressing Znf217+ EAC had increased tumor volume over controls, suggesting that mice overexpressing Znf217 developed resistance to the EAC chemotherapy. To overcome breast cancer chemoresistance caused by ZNF217 overexpression, we identified triciribine, a nucleoside analog and AKT inhibitor, as a drug that kills cells that overexpress ZNF217. We have used our preclinical animal models of Znf217 overexpression to elucidate the appropriate dosing for combination therapy of triciribine and the microtubule inhibitor paclitaxel to treat breast cancer. We found that the treatment order impacts the therapeutic efficacy. This study will directly influence the design of Phase II clinical trials with triciribine and paclitaxel in metastatic breast cancer patients.