Project: Proteogenomic and targeted metabolomic analysis of ovarian cancer heterogeneity and its contribution to recurrence and therapy resistance.

Acronym	PROMETOV (Reference Number: TRS-2015-00000149)
Duration	01/09/2016 - 01/09/2019
Project Topic	Background: Despite major progress in cancer therapy, mortality from ovarian cancer has changed only marginally in the past 30 years. While aggressive primary therapy including radical surgery and platinum-based chemotherapies gain response rates of >70%, most tumors relapse, leading to a dismal prognosis. Hypothesis: The relapse after an initial treatment response suggests that tumor heterogeneity may be involved in the therapy resistance of ovarian cancer. Specifically, differences between cells from the primary tumor and the metastatic disease in the same patient before and after therapy may explain why the initial response is mostly followed by tumor recurrence. Aims: Our aim is to develop minimally-invasive methods to monitor tumor evolution through biological fluids which are expected to better capture tumor heterogeneity than single tumor biopsies and thus to overcome tumor sampling bias. This will aid in early detection, monitoring of therapy efficacy and detection of recurrence in ovarian cancer. Methods: Plasma as well as tissue from the primary tumor and peritoneal metastases will be collected from patients with primary inoperative ovarian cancer who undergo surgery before and after systemic neo-adjuvant treatment. Tumor heterogeneity in the primary tumor and metastases before and after therapy will be measured by a novel proteogenomics, phospho-proteomics and targeted metabolomics approach using RNASeq as well as tandem mass spectrometry and chemical isobaric labelling with Tandem Mass Tags™ (TMT). TMT enables the simultaneous measurement of up to ten samples in one experiment. For biomarker identification, TMT-based simultaneous measurements of heterogeneous tumor tissues as well as biological fluids will be performed. These proteomics and targeted metabolomics measurements will identify the molecules present in both compartments while also dramatically increasing the sensitivity of the measurements. While most multi-omics studies neglect metabolomics, we will include targeted metabolomics with a focus on tryptophan metabolism, as we have preliminary evidence that this pathway plays an important role in ovarian cancer immune evasion. Tailored tools and computer pipelines will be developed for data analysis and the predicted biomarkers will be validated in prospectively collected biological fluids by targeted analyses. Expected results and potential impact: PROMETOV will enable an improved understanding of the contribution of ovarian cancer heterogeneity to therapy resistance and tumor recurrence and provide the basis to identify minimally-invasive sampling methods for early ovarian cancer detection, therapy monitoring and detection of relapse. If successful in the clinic such biomarkers would have an immense impact as they would enable early therapy, stratification of patients to treatments and control of treatment responses.
Network	TRANSCAN-2
Call	Joint Transnational Call for Proposals (JTC 2014)

Project partner

Number	Name	Role	Country
1	German Cancer Research Center, DKFZ	Coordinator	Germany
2	Proteome Sciences R&D GmbH & Co. KG	Partner	Germany
3	Istanbul Medical Faculty, Istanbul University	Partner	Türkiye
4	University Medical Centre Lubljana	Partner	Slovenia
5	Bar Ilan University	Partner	Israel
6	University of Groningen	Partner	Netherlands
7	Tartu University Hospital	Partner	Estonia