Inflammatory bowel diseases (IBD), colorectal cancer (CRC) and gastric cancer (GC), still remain disease entities with a high morbidity burden and are major contributors to health problems worldwide.
The burden of IBD is rising globally with substantial variation in levels and trends of disease. Most available therapies with biologicals are directed against the inflammatory responses, but still a substantial number of patients fail to respond or to obtain full remission. In a later stage, some patients will even need surgery and are facing an increased risk of developing colon cancer.
GC and CRC are respectively the third and fourth leading cause of cancer deaths worldwide, as prognosis in the advanced tumour stage still remains poor. While chemotherapy is the cornerstone of cancer therapy, limited efﬁcacy and development of resistance to chemotherapeutic drugs are major challenges in the treatment of these epithelial cancers. Next to this, immunotherapy does not provide major advances in metastatic CRC and GC as the response rate still remains low.
One way to improve treatment, is focussing on personalized medicine where efforts must be directed towards the identification of patients who are likely to respond to a specific treatment regimen and optimize its efficacy. This personalization can focus on molecular biomarkers to maximize efficacy and minimize adverse events. Ideally, such biomarkers should have both a prognostic and predictive potential. Assessment of mucosal healing upon therapy is the golden standard to validate treatment efficacy in IBD, but validated markers for disease monitoring have still their limitations. Furthermore, knowledge of the molecular basis of CRC and GC has advanced at a rapid pace in recent years, which led to the identification of potential biomarkers. However, due to the large heterogeneity of these cancer types, such markers are not present in the majority of cancer patients, resulting in restricted efficiency for clinical application.
Novel markers that could fit these criteria are the transmembrane MUC1 and MUC13 mucins. Both mucins are highly overexpressed in IBD, CRC and GC patients, making them valuable new markers for clinical implementation. Furthermore, mucins are highly polymorphic and the presence of genetic differences in the MUC1 and MUC13 genes can result in several mRNA isoforms of which some can be implicated in disease. The MUC1 and MUC13 mRNA isoforms associated with IBD, GC and CRC still remain an unexplored conundrum. We have recently performed a proof of concept study in which we identified the MUC1 and MUC13 mRNA isoforms associated with inflammation in IBD. We wish to build upon these data and extend our search to unravel the MUC1 and MUC13 mRNA isoforms as biomarkers to improve follow-up and treatment in IBD, CRC and GC. Therefore, in this project, we will develop and validate a novel biomarker assay, based on MUC1 and MUC13 mRNA isoforms with prognostic and predictive potential, to predict disease outcome and therapy response in IBD, CRC and GC. To do so, we will unravel the MUC1 and MUC13 mRNA isoforms aberrantly expressed in IBD, CRC and GC patients and correlate their expression levels with clinical patient data. Thereafter, we will generate a multiplex RT-qPCR based on a selected isoform panel and validate our assay on tissue and liquid biopsies to evaluate the efficacy of the isoforms as non-invasive prognostic and predictive biomarkers.