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.
- 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