Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer but also affects adults. Many patient subpopulations are over-treated, leading to long-term side effects, while others are resistant to therapy or prone to relapse. Patients who relapse or experience post-treatment complications have poorer survival outcomes. Therefore, biomarkers are needed to stratify more efficient targeted therapies to the right patients. We have recently shown that combining quantitative proteomics and pioneering thermal proteomics with drug response profiling can identify unexpected subtype-specific vulnerabilities, better capturing cellular phenotypes linked to targeted drug sensitivity. Notably, we have advanced the mechanistic understanding of bryostatin-1, a potential targeted therapy for MEF2D-rearranged high-risk patients. Our data suggest that bryostatin-1 engages the MAPK pathway while simultaneously altering TCF3 and MYC activity through epigenetic regulation, highlighting a dual mechanism of action. We now aim to evaluate these therapies in more clinically relevant experimental settings, including multi-omics analysis of 30 PDX models and 145 clinical ALL samples and an additional 137 ALL cell lines. Integrating structural variants, epigenetics from WGS, and post-translational modification on proteome level will further enhance our ability to identify biomarkers and mechanisms. Collectively, this large resource and project seeks to deepen our understanding of ALL biology, paving the way for viable precision medicine opportunities that benefit ALL patients.