Harnessing DNA Replication Stress to Overcome Treatment Resistance of high-risk Cancers

The landscape of precision medicine in cancer is on the brink of a profound shift, propelled by rapid advancements in next-generation anticancer drugs, including immuno-oncology (IO) and DNA repair therapies.

Our project aims to pioneer therapeutic strategies targeting factors regulating decisive cellular programs to combat resistance mechanisms and relapse.We propose that ubiquitin ligases represent promising targets for high-risk cancer patients by degrading crucial regulatory components within the replication stress (RS) response program and core transcription factor networks.We´ve assembled a team of leading scientists in ubiquitin research, DNA repair, cancer biology, and drug discovery to execute this project.

Utilizing innovative methodologies such as multi-omics profiling, target-specific live-cell ubiquitin screens, and computational biology, alongside animal models and molecular analyses, we aim to achieve all objectives within the next four years.

These include i) providing experimental evidence that suppression of RS is a vulnerability in osteosarcoma and neuroblastoma, ii/iii) identifying compounds targeting RS-tolerance mechanisms to unleash immune activation and sensitize tumors to IO drugs, and iv) developing therpeutic strategies to prevent drug resistance and relapse in leukemia.This project will lay the foundation for novel combination therapies improving the survival of poorly immunogenic and drug resistant cancers.