Header Forschung

Preclinical evaluation of innovative targeted therapies in an ovarian cancer mouse model

Summary of the Project

Ovarian cancer is the leading cause of death among female gynecologic malignancies and its mortality rate has changed only marginally over the past 30 years. Clinically relevant risk factors for ovarian cancer are age and BRCA 1/2 germline mutations causing an ovarian cancer lifetime risk >56%. Standard treatment of advanced ovarian cancer constitutes primary surgery aiming at macroscopic complete tumor resection and subsequent platinum- and paclitaxel-based chemotherapy.

It was shown that patients with a BRCA-deficiency and recurrent serous ovarian cancer can have a benefit from PARP-inhibitors. Apart from this, primary resistance to platinum-based chemotherapy, observed in about 15-20% of patients, constitutes one of the most recognized clinical challenges for ovarian cancer.

Usually, antitumor chemotherapy is unsuccessful if resistance against a given drug occurs. So called “duplex drugs” may present a promising alternative for combinatory therapeutic schedules.  Our first therapeutic approach, which we investigate in collaboration with Dr. Sarah Schott (NCT Heidelberg), is a novel concept of a polychemotherapy and consists of the duplex drug 2‘-Deoxy-5-fluorouridylyl-C-ethynylcytidin (5-FdU-ECyd). Moreover, we will analyze tyrosine kinase inhibitors of the BMP-signaling pathway and other small molecule inhibitors as potential platinum-sensitizers.

These novel therapeutic approaches will be tested in an intraperitoneal ovarian cancer mouse model. Particularly, we will address the clinically relevant question, whether these novel therapeutics may be suitable in the platinum-resistant or BRCA1-deficient situation. Finally, by testing rational combinations, we want to interrogate whether these candidate drugs may improve efficacy of the PARP-inhibitor Olaparib in our ovarian cancer models.

Scientific Goals

  • Improve the clinical management of patients with platinum-resistant ovarian cancer with innovative targeted approaches
  • Improve spectrum of application and efficacy of PARP-inhibitors in ovarian cancer patients with rationally combined targeted therapy approaches
The figure shows a “false-colour” image of an immunodeficient mouse, xenografted with human ovarian cancer cells. Localization of tumor cells was detected by luciferase imaging.

The figure shows a “false-colour” image of an immunodeficient mouse, xenografted with human ovarian cancer cells. Localization of tumor cells was detected by luciferase imaging.
Copyright: Molekulare Gynäkologische Onkologie, Uniklinik Dresden

Kuhlmann JD, Wimberger P, Wilsch K, Fluck M, Suter L, Brunner G. Increased level of circulating u2 small nuclear rna fragments indicates metastasis in melanoma patients. Clinical chemistry and laboratory medicine : CCLM / FESCC 2015;53:605-11.

Kuhlmann JD, Wimberger P, Bankfalvi A, Keller T, Scholer S, Aktas B, et al. ERCC1-positive circulating tumor cells in the blood of ovarian cancer patients as a predictive biomarker for platinum resistance. Clinical chemistry 2014;60:1282-9.

Wimberger P, Chebouti I, Kasimir-Bauer S, Lachmann R, Kuhlisch E, Kimmig R, et al. Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance. Gynecologic oncology 2014;133:467-72.

Kuhlmann JD, Baraniskin A, Hahn SA, Mosel F, Bredemeier M, Wimberger P, et al. Circulating u2 small nuclear rna fragments as a novel diagnostic tool for patients with epithelial ovarian cancer. Clinical chemistry 2014;60:206-13.

Kuhlmann JD, Schwarzenbach H, Wimberger P, Poetsch M, Kimmig R, Kasimir-Bauer S. Loh at 6q and 10q in fractionated circulating DNA of ovarian cancer patients is predictive for tumor cell spread and overall survival. BMC cancer 2012;12:325.

Contact

Prof. Pauline Wimberger
Director, Department of Gynecology and Obstetrics
Phone: +49 351 458 6728
Email: pauline.wimberger(at)uniklinikum-dresden.de

Dr. Jan Dominik Kuhlmann
Head of Laboratory, Department of Gynecology and Obstetrics
Phone: + 49 351 458 2434
Email: jan.kuhlmann(at)uniklinikum-dresden.de