Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.


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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Publication Info

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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David John Adams

Adjunct Associate Professor in the Department of Medicine

A major ongoing challenge in cancer therapy is development of selective chemotherapeutics that can eradicate tumors with little or no side effects to the patient. Most of our current arsenal of anti-cancer drugs was developed to simply target replicating cells. Thus, while these drugs do kill tumor cells, they are also toxic to normal replicating cells in the body, such as those found in the bone marrow and in the lining of the intestines. Recent advances in tumor biology indicate that the environment surrounding tumor versus normal cells is different and can be exploited to improve anti-cancer drug selectivity. Specifically, solid tumors have a defect in metabolism of glucose that leads to the secretion of lactic acid. This forms an acidic microenvironment and accompanying pH gradient in tumor cells that is not present in normal cells. Our laboratory, in collaboration with investigators at Duke, Research Triangle Institute International, the National Cancer Institute, and DEKK-TEC, Inc. are developing analogs of the plant toxin, camptothecin, that are selectively active at acidic pH. To date, we have identified six such compounds, one of which is highly fluorescent and can be quantified by external biosensors to permit study of tumor pharmacokinetics and pharmcodynamics in situ in real time. This agent has remarkable activity in a pre-clinical model of pancreatic cancer and is currently being advanced to IND status for subsequent biomarker-based clinical evaluation. In addition to solid tumors, we collaborate with clinical oncologists in the Duke Division of Cell Therapy on translational research in leukemia and lymphoma. In particular, we are interested in optimizing combination chemotherapy regimens for established and novel drugs in stem/progenitor models of acute myelogenous leukemia. The overall objective is to move drug discovery and development toward more clinically relevant models that can help bridge the "valley of death" - barriers that currently limit translation of laboratory advances into clinical utility for cancer patients.


Andrew Benjamin Nixon

Professor in Medicine

Andrew Nixon, PhD, MBA (Professor of Medicine) is Director of the Phase I Biomarker Laboratory, which brings together clinical, translational and basic research to pursue the development of novel biomarkers defining mechanisms of sensitivity, resistance, and toxicity to given therapeutic drug classes, particularly anti-angiogenic agents. Additionally, the laboratory has been appointed as a Molecular Reference Laboratory for the Alliance oncology cooperative group, a national clinical trial research group sponsored by the National Cancer Institute. The laboratory has quality control procedures in place to address many of the issues involved in clinical trial research including determination of sample quantity, sample integrity, and sample heterogeneity. We have spent considerable time developing robust assays that utilize limited amounts of specimen while providing high quality data. Multiplex ELISA and gene expression arrays are used to analyze serially collected blood and paraffin samples archived from cancer patient clinical trials. This work has the potential to improve the efficacy and toxicity of current therapies and to guide the development of the next generation of anti-angiogenesis therapies for cancer and other diseases.


Angeles Alvarez Secord

Professor of Obstetrics and Gynecology

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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