Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.
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2014
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BACKGROUND: To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway. METHODS: SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated. RESULTS: Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1. CONCLUSION: Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.
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Lopez-Acevedo, Micael, Lisa Grace, Deanna Teoh, Regina Whitaker, David J Adams, Jingquan Jia, Andrew B Nixon, Angeles Alvarez Secord, et al. (2014). Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines. Gynecol Oncol Res Pract, 1. p. 2. 10.1186/2053-6844-1-2 Retrieved from https://hdl.handle.net/10161/12496.
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Andrew Benjamin Nixon
Dr. Andrew Nixon is Professor of Medicine in the Department of Medicine/Division of Medical Oncology at Duke University. He holds a BS in chemistry from Miami University, a PhD in biochemistry from Wake Forest University, and an MBA with a focus on healthcare management from Duke University/Fuqua School of Business. He is a nationally recognized expert in the development of cancer biomarkers and correlative science, with extensive experience leading large multi-center biomarker analyses. Dr. Nixon serves in various leadership roles within the National Cancer Institute (NCI), working with diverse multi-disciplinary teams focused on improving cancer patient outcomes through biomarker science. He serves as the national co-chair for the NCI Core Correlative Sciences Committee which adjudicates the use of biospecimens collected throughout the NCI National Clinical Trial Network (NCTN). Within the NCI-NCTN Alliance cooperative group, Dr. Nixon has multiple leadership positions including serving on the Alliance Board of Directors, co-chair of the Immuno-Oncology Committee, co-chair for Gastrointestinal Correlative Research, and has been an executive member of the Translational Research Program since its inception. Additionally, within the NCI-NCTN NRG cooperative group, he serves as a member of the Gynecologic Translational Science Committee and on the Gynecological Oncology Group - Partners Investigator Council Translational Research Subcommittee. Dr. Nixon is an American Society for Clinical Oncology (ASCO) Ambassador and has chaired various committees and led scientific and educational sessions at national conferences. Recently, Dr. Nixon has focused his research on cellular senescence and biomarkers of aging and early carcinogenesis. He serves as Principal Investigator for a large multi-center NIH grant to develop high-resolution tissue maps and biomarkers of cellular senescence as a part of the Senescence Network (SenNet) Consortium.
Angeles Alvarez Secord
My primary research interest has focused on on novel therapeutics, biomarkers and clinical trial development for ovarian and endometrial cancer. My fundamental goal is to develop a strong translational research program at Duke University in the Gynecologic Oncology Division, where knowledge we glean from our basic science research can be incorporated into our clinical trial program. Specifically, my focus is on biologic therapy and molecular biomarkers to direct therapy in patients with ovarian and endometrial cancers to determine if a strategy that incorporates both clinical and genomic information can improve clinical outcome, minimize unnecessary toxicity, and impact positively on quality of life.
In addition I am interested in robotic-assisted laparoscopic surgery for women with endometrial, ovarian and cervical cancers, as well as for benign gynecologic conditions.
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