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Identification of genetic markers for everolimus-resistance in patients with pancreatic neuroendocrine tumors

Everolimus is a targeted therapy commonly used for patients with advanced pancreatic neuroendocrine tumors (PNETs). Unfortunately, after a while patients develop resistance, seen as progression on medical images. Earlier detection of resistance allows a quicker change to more effective therapies, results in better patient outcome, spares patients from ineffective treatment and reduces costs for society. Building on cell line data, fusion genes will first be studied in everolimus-naïve PNET patients as they may represent interesting genetic markers. For further experiments, tissue and monthly blood and urine samples from 30 PNET patients starting everolimus treatment will be collected (EVEREST trial). To identify the first resistance-predicting mutations, the DNA sequence of tumor tissue before and after everolimus-resistance will be compared. Next, we will study the possibility of detecting predictive mutations in non-invasively obtainable tumor DNA fragments in blood and urine (CtDNA) and of using serial CtDNA level measurements as a follow-up marker, both aiming at earlier detection of everolimus-resistance. CtDNA level is estimated by detection of tumor-specific mutations in serial plasma and urine samples. These mutations should be present at baseline and are selected based on the tumor's genetic profile, the experiment on fusion genes, previously obtained results and literature. We expect to detect a rise in CtDNA level when resistance develops.
Date:1 Oct 2017 →  30 Sep 2019
Disciplines:Morphological sciences, Oncology
Project type:Collaboration project