February 14, 2023

Dissect Longitudinal Evolutionary Trajectories in Ovarian Cancer Patients Using Integrated Proteogenomics

3rd Call, Pioneer Project

Short Summary

In the era of personalized medicine where we transition from organ-based diagnosis towards individual genetically-linked diseases, the tailoring of treatment in cancer is increasingly important. This is particularly true for adenocarcinomas of the gynaecological tract where novel treatment options are urgently needed. Our project aims to identify mechanisms of disease recurrence by using integrated proteogenomics in a matched and longitudinal patient cohort. Differences identified herein will gain valuable insights into disease progression with the opportunity to identify molecular signatures for future intervention.

Goals

The anticipated project utilizes a unique cohort comprising of high-quality cancer samples from different sites (tubo-ovarian, omentum, peritoneum, and ascites) and time points (primary diagnosis and recurrence) to gather proteogenomic data on cancer metastasis and disease recurrence. Exome sequencing combined with RNA sequencing and proteomics will allow to identify chemotherapy responders, mechanisms of disease recurrence and generate a comprehensive multi-omic data.

Significance

Gynaecological cancers, and in particular adenocarcinomas of the ovary, tube and peritoneum are aggressive malignant diseases with a poor overall survival. It is of importance to better understand the heterogeneity of this disease in order to identify personalized treatment options. Results obtained herein allow to improve discussions in molecular tumor boards and stratify patients as well as targeted treatment due to this molecular phenotype at each individual stage of the disease. Integration of proteomic measurements with genomics, protein complex disturbances caused by exome mutations and association between proteins and chromosomal instability could also lead to insights into how different copy-number alternations influence the proteome.

Background

The treatment of malignant diseases has changed significantly with the appearance of diagnostic and targetable cancer markers in the last two decades. Despite remarkable advances in molecular medicine accompanied with advanced drug development, only a limited number of patients show a clear benefit from targeted therapies which is in particular true for aggressive high-grade ovarian cancer. Standard chemotherapy using Carboplatin and Paclitaxel is usually given either neoadjuvant before interval debulking or after initial maximal debulking surgery in the adjuvant setting. Additional drugs have been evaluated in clinical trials in the primary and recurrent maintenance treatment setting. There were also improvements on progression-free survival using anti-VEGF antibodies and PARP inhibitors, however, the underlying molecular signatures leading to disease recurrence remain to be elucidated and are of increasing debate nowadays.