Highlight of the Importance of Translational Medicine in Ovarian Cancer
Hani Gabra, Professor of Medical Oncology at the Department of Surgery & Cancer at the Imperial College in London gave a talk during the EUTROC/ENTRIGO session at the ESGO meeting on Sunday September 11, 2011. The European Network for Translational Research in Ovarian Cancer (EUTROC) was created to improve the current and future management of ovarian cancer (http://www.eutroc.org). The goal of EUTROC is to create a multidisciplinary platform by bringing together the complexity of basic science to study the mechanism underlying ovarian cancer and its progression with its application through patient clinical trials. Essentially, EUTROC brings translational researchers in Europe together to facilitate “bench to bedside” research and vice versa.
Professor Gabra stressed the importance of translational research in light of the current hurdles that face ovarian cancer researchers. These include a lack of an integrated, "systems biology" approach to the study of ovarian cancer, a lack of a translation from basic science to clinical studies, and a lack of ovarian cancer models to study the mechanism of the disease. He presented the goals of the European Network of Translational Research In Gynaecological Oncology (ENTRIGO), which was formed through ESGO as being: to establish a network of biobanks of patient samples to facilitate research, and to focus on new predictive/prognostic biomarker development in order to facilitate the monitoring of treatment and execute clinical trials that take advantage of the biobanks and biomarker research. The long-term goal of ENTRIGO is to develop at least two innovative tests, techniques or devices, which will be applied to clinical routine care for women-specific cancers within the next 10 years.
“We don’t do well in turning our science into new patient benefit,” said Professor Gabra, and stressed the importance of well-executed, enhanced larger scale phase 2 trials, on the order of 100 to 250 patients, that will test hypotheses and include target validation. These trials, according to Professor Gabra, should be performed in both academic centers and the community in order to better integrate community oncologists into innovative research. “We need to develop information to design better effective pivotal trials,” he stated. Importantly, these trials should provide a firm “go/no go” decision for large-scale phase 3 development.
He believes that the effort should focus on predictive algorithms, which can help determine whether a patient will respond to a specific treatment, in order to enrich a clinical trial population and see a real and lasting effect of a treatment, rather than concentrating on prognostic factors.
Professor Gabra presented his translational, unpublished work on the “mechanisms of chemotherapy resistance in ovarian cancer." The research focuses on using cell lines; the hypothesis is that platinum-sensitive clones within the tumor exist prior to treatment and are enriched following relapse after a platinum-based chemotherapy regimen. The idea is that at relapse, the disease that manifests is a second disease from a dominant clone that has existed, but in smaller numbers, during the original presentation of the cancer. Because ovarian cancer comes back in over 70% of patients, research to understand the underlying mechanism of chemotherapy resistance is highly important. So far, the research shows that the AKT pathway is activated in platinum-resistance ovarian cancer cells.
“AKT does something very different in the platinum-resistant cells but not in isogenic platinum-sensitive cells…and this is not a PI3 kinase dependent AKT change. So this means that we need to think differently about treatment in platinum-resistant disease. PI3 kinase drugs are not interchangeable in platinum sensitive and platinum-resistant cells” he explained. The current focus of the research is to further understand the AKT-based mechanism of resistance and to begin clinical trials with various targeted agents to test their hypotheses.
Classification of epithelial ovarian cancer
During the plenary session, on Monday September 12, 2011, Dr. Charlie Gourley of the University of Edinburgh Cancer Research Centre presented novel research on ways to differentiate epithelial ovarian cancer (EOC), which is mostly treated as a single disease but is in fact an histologically and phenotypically heterogeneous group of diseases. Microarray expression analysis of EOC samples demonstrated six different subgroups of EOC that were linked to their underlying histology and overall survival. The serous subtype was highly correlated with vasculature development and the angiogenesis process. The overall goal of the research is to identify new molecular subgroups of EOC to take advantage of their unique characteristics for targeted treatments. For example, the angiogenesis genes that appear to be upregulated in the serous EOC subtype may be linked to this type of tumor’s response to bevicizumab, seen in the GOG218 and ICON7 trials.
Detecting and characterizing circulating tumor cells
At the late-breaking oral presentation session on Wednesday, September 14, 2011, researcher Eva Obermayr of the Department of Obstetrics and Gynecology, Medical University of Vienna presented a talk on the molecular markers used to detect circulating tumor cells (CTCs) in ovarian cancer patients.
CTCs are generally precursors to metastatic lesions, have a clinical impact in cancers, and have been detected in breast, colorectal, lung, and liver cancers, among others but are not well-studied in ovarian cancer. The challenge of their detection is that they are rare events among white blood cells and better enrichment and detection technologies are needed in order to identify them.
The overall goal of the study is to find early molecular traces that may indicate recurrence of ovarian cancer. Peripheral blood samples from ovarian cancer and healthy subjects as well as tumor tissue were taken and subjected to a whole genome expression. 11 genes that were highly expressed in the tumor tissue but not in the normal tissues were measured in the blood fraction of cancer patients with advanced EOC, both before primary treatment and after adjuvant chemotherapy. CTCs were detected in ~25% of the pre-treatment patients and ~20% of the post-treatment samples. CTC presence was correlated with sub-optimal debulking and presence of ascites before treatment. After treatment, CTCs occurred more often in older age patients (P = 0.016), those with a higher FIGO stage of cancer (P = 0.035), and those with chemo-resistant disease (P = 0.035).
Cyclophilin C (CypC) was the most frequently overexpressed gene marker in both pre-treated and post-treated samples, followed by the GPX8 (probably glutathione peroxidase 8) gene in the pre-treated samples. CYpC functions in protein folding and apoptosis. Overexpression of CypC in cancer cells has been previously shown to result in resistance to hypoxia and cisplatin-induced cell death.
Patients with CPC-positive disease generally had a shorter disease free (pre-therapeutic, P= 0.033; post-therapeutic, P = 0.046) and overall survival (pre-therapeutic, P = 0.018; post-therapeutic, P = 0.104). CTC presence was an independent prognostic factor for shorter disease-free survival and overall survival (pre-therapeutic P = 0.014, post-therapeutic P = 0.129). The authors concluded that the presence of CTCs in ovarian cancer patients results in an overall worse outcome and further characterization and utility of CTCs as a marker of prognosis are ongoing.