Papillary serous ovarian cancer is among the five most lethal cancers affecting women in the U.S. While ovarian cancers initially respond well to chemotherapy involving platinum and taxol-based agents, most cancers eventually recur as platinum-resistant disease that is no longer amenable to currently available chemotherapeutic drugs. Therefore, ovarian cancer progression and acquired drug resistance are intricately linked processes, and many of the genes that promote cancer growth have also been implicated in drug resistance. Understanding the molecular mechanisms involved in acquired drug resistance is paramount to the design of novel therapies that target the genes maintaining drug resistance. Here, we propose to study tumor evolution under the selection pressure of chemotherapy in a mouse model of ovarian cancer. Human ovarian cancers will be propagated in mice and exposed to conventional chemotherapy or targeted therapy. The goal is to select for cancer cells that become resistant to the given chemotherapeutic agent. Using molecular profiling techniques, we will then compare the resulting tumors from different treatment groups to each other and to the original specimen, in order to identify genetic events that occurred during the drug selection process. Specific genes that become activated during tumor evolution will be characterized in the context of drug resistance and tumor progression. Finally, we will assess if the activation of novel drug resistance genes correlates with clinical parameters, such as survival. Taken together, we hope that these studies will contribute to the molecular understanding of ovarian cancer and help translate this knowledge into clinical applications.
This grant was made possible in part through a generous donation from OCRF Board member Susie Fragnoli.
Dr. W. Ruprecht Wiedemeyer is a Research Scientist at Cedars-Sinai Medical Center in Los Angeles. He joined the faculty of Cedars-Sinai’s Women’s Cancer Program in late 2009 and is a member of the Samuel Oschin Comprehensive Cancer Center. In 2010, he was also appointed Assistant Professor at the University of California, Los Angeles.
Dr. Wiedemeyer received his undergraduate training in Germany and holds a doctorate degree in molecular cancer genetics. As a graduate student in Manfred Schwab’s laboratory at the German Cancer Research Center, he worked on the transcription factor N-Myc and cell death genes in the pediatric cancer, neuroblastoma. Towards the end of his Ph.D., Dr. Wiedemeyer received a Klaus Tschira stipend to pursue postgraduate studies in bioinformatics at the University of Karlsruhe, Germany. Upon completion of this training, he joined Lynda Chin’s lab at the Dana-Farber Cancer Institute/Harvard Medical School in Boston. As a postdoc in Dr. Chin’s group, he combined array-based profiling techniques, bioinformatics and biochemistry to characterize the genomes of malignant brain tumors (glioblastomas). In addition, Dr. Wiedemeyer took part in The Cancer Genome Atlas (TCGA) pilot project. Studying different types of cancer, the focus of his work has been on the molecular pathways that are recurrently altered across various forms of cancer. Of particular interest are genetic events that can predict the response of a tumor to chemotherapeutic agents. In his current project, Dr. Wiedemeyer will investigate the genetic changes that enable human ovarian cancers to become resistant to chemotherapeutic agents targeting specific cancer-relevant pathways.