Research Questions:
1. Can we infer latent biology predisposing cancers to drug off-target effects?
2. How do tumors respond to (systemically high) drug off-target toxicity?
Objectives:
1. Linking Drug Adverse Events to Tumor Progression:
Objective: To elucidate the correlation between drug adverse events (AEs) derived from Electronic Health Records (EHRs) and tumor progression markers in the UK Biobank cancer cohort.
Specific Aim: Identify potential latent biological factors that predispose cancers to drug off-target effects.
2. Construction of a Pan-Cancer Drug Off-Targetome:
Objective: To establish a comprehensive off-targetome by integrating on-target and off-target effects of drugs using multi-modal analysis of over 1,000 cancer cell lines and 600+ anti-cancer agents from datasets such as DepMap and GDSC.
3. Inference of Non-Genetic Drug Resistance:
Objective: To derive non-genetic drug resistance signatures associated with off-targetome signatures using low-burden mutation signatures (Msigs).
4. Phenotypic Screens and In Vivo Validation:
Objective: To perform phenotypic screens of drug-tolerant persisters (DTPs) in vitro and validate the findings in vivo using KRAS-DTP models.
Specific Aim: Investigate how off-target drug toxicity primes diverse TGFB-responsive DTP states and promotes chromatin states that mark highly disordered factors in DTPs.
Scientific Rationale:
Cancer relapse remains a significant challenge in oncology, often driven by non-genetic resistance mechanisms. Understanding how drug off-target effects influence tumor biology and contribute to relapse is crucial for developing more effective therapies. This project aims to uncover the latent biology underlying drug off-target effects and their role in priming non-genetic resistance pathways in cancer. By leveraging the rich EHR and omics data from the UK Biobank cancer cohort, we aim to identify novel therapeutic targets and improve patient outcomes.