GLIO-COMBO Targeting tumor heterogeneity in pediatric high-grade glioma

Pediatric high-grad gliomas (pHGGs) are a rare but very aggressive type of brain cancer in children. They account for about 10% of childhood brain tumors, but are responsible for over 40% of brain cancer- related deaths in children. Current treatment comprises radiation and chemotherapy but unfortunately, these approaches cannot cure the disease. While they may slow tumor progression for a time, sadly, fewer than 10% of affected children survive more than two years after diagnosis. The complex biological structure and behavior of pHGGs play a major role in why treatments eventually stop working. The GLIO-COMBO project is based on the hypothesis, that the biological diversity within and between pHGGs is one of the main reasons why treatment fail and tumors develop resistance. However, this same diversity could also be the key to discovering new treatment strategies. Our goal is to turn this knowledge into smarter, more personalized combinations of treatments that work more effectively and help prevent tumor regrowth. The GLIO-COMBO project will focus on three main steps: 1) We aim to understand tumor resistance. Thus, we will study how differences between tumor cells help them survive treatment. By applying advanced sequencing techniques, we can examine individual tumor cells before and after therapy through innovative preclinical models. 2) We will develop new drug combinations. Using the knowledge about tumor cell diversity, we will identify drugs that target the specific weaknesses of treatment- resistant pHGG cells. These drugs will be tested alone or in combination with standard therapies on lab- grown tumor models. 3) We will validate promising treatments. The most effective drug combinations will be tested in advanced preclinical systems, including mini-brain tumor models (called organoids) that allow tumors grow in a small brain-like structure in a dish, as well as in animal models that closely mimic the nature of pHGG. What makes GLIO-COMBO different is the use of realistic tumor models derived from patient samples and advanced genetic tools. These models allow us to study the full complexity of pHGGs, something that has not been possible at this scale before. By doing so, we hope to uncover new weaknesses in these tumors that we can attack with tailored combination therapies. The GLIO-COMBO consortium aims to provide oncologists with new insights to better understand each childs individual tumor and to offer more effective, targeted treatment options in the future. Ultimately, our mission is to improve survival rates and quality of life for children facing one of the most devastating types of brain cancer