Resistance evolution in solid paediatric cancers with HRD

Although rare, cancer remains one of the leading causes of death in children. A major reason is that some cancers become resistant to treatment. This often happens because cancers can evolve and change, in a process similar to Charles Darwins theory of natural selection. Cells that have traits that allow them to survive treatment begin to take over, making the disease harder to control. When this happens, doctors often have to change their approach. New drugs bring new hope, but resistance can still emerge. One promising treatment for childhood cancers is a class of drugs called PARP inhibitors. These drugs target cancer cells that struggle to repair their DNA. In our project, RECHORD, we aim to understand how childhood cancers become resistant to PARP inhibitors. We will do this by recreating the process of evolution in the lab and studying, cell-by-cell, how cancer adapts to this therapy. We already know that childhood cancers have different mutations compared to adult cancers, and we believe they may also resist treatment in different ways. Additionally, we want to find out whether the cells that survive PARP inhibitors develop new weaknessesvulnerabilities we can target to stay ahead of the disease. To explore this, well use state-of-the-art methods to study how cancer cells change. Well look at their DNA, whether their genes are being turned on or off, and how their DNA is organized inside the cell. Each of these layers gives us clues about how the cancer is evolving and how we might stop it. For example, if resistance is caused by new mutations, we might find new drug targets. If its caused by cells becoming more flexible in how they behave, we may need entirely new strategies. By understanding how childhood cancer cells evolve, we hope to uncover insights that could shape future treatments. Our approach is inspired by evolution itselfwell trace the family trees of cancer cells to understand why some respond to treatment while others dont. Our team brings together experts in cancer biology, genetics, and bioinformatics to take on this challenge. We aim to uncover how cancer cells respond to new drugs, especially in high- risk childhood cancers, by recording the many ways they adapt and survive. The knowledge we gain wont just help the specific cancers we studyit will also deepen our general understanding of how resistance develops in cancer. If successful, RECHORD could help us better predict how a patients disease might progress on PARP inhibitorsand offer new ways to fight back if resistance arises.