Combating the therapy-induced resistance in tumors of the upper gastrointestinal tract

Esophageal adenocarcinoma (EAC) and pancreatic ductal adenocarcinoma (PDAC) are among the most aggressive malignancies of the upper gastrointestinal tract. A key challenge in their treatment is therapy-induced resistance, which contributes to high recurrence rates and poor patient outcomes. This dissertation centers on overcoming acquired resistance by exploring novel therapeutic strategies.
We introduced promising targeted therapies integrated with chemo(radio)therapy to enhance treatment efficacy. To evaluate these strategies, we utilized diverse models, including primary cell lines and patient-derived xenograft mouse models. By mapping the heterogeneity in therapeutic responses, we identified predictive biomarkers to aid in patient stratification and personalized treatment selection. In this process, our research combined conventional in vitro experiments with computational approaches, leveraging large-scale omics datasets and real-world clinical data.
The findings uncover the intricate mechanisms underlying therapy resistance and disease recurrence in EAC and PDAC while presenting innovative multimodal treatment strategies, such as incorporating hyaluronidase into anti-angiogenesis regimens and combining TGF-β inhibition with chemo(radio)therapy. Additionally, this work emphasizes the development of in vitro and in vivo models that effectively mimic the complex interactions between tumors and the surrounding tumor microenvironment.
Ultimately, this dissertation advances our understanding of therapy resistance in upper gastrointestinal tumors and contributes to the development of novel treatment regimens. By integrating biomarker-driven strategies with targeted therapies, this research supports the advancement of precision medicine, aiming to improve patient outcomes through more effective and personalized treatments.