GARD: Genomic Data based Drug Repurposing in Head and Neck Cancer with Large Language Model Validation

Head and neck cancer (HNC) represents the seventh most common cancer diagnosis globally, yet current treatments, including surgery, radiation, and immunotherapy, have shown limited improvement in outcomes. Drug repurposing offers a cost-effective strategy to identify new therapeutic options by leveraging existing medications with known safety profiles. Within this study we developed the GARD pipeline (Genomic Alteration-based Repurposing for Drugs), designed to uncover repurposing candidates for HNC using genomic and network-based approaches.

GARD integrates multi-omics data from The Cancer Genome Atlas (TCGA), including copy number variation (CNV) and somatic mutations (SOM). The cohort was stratified by human papillomavirus (HPV) status. Risk-associated genes were identified and then expanded via high-confidence protein-protein interaction (PPI) networks. Top candidate genes were filtered through comprehensive analysis of publicly available literature data in PubMed using LLM to validate the relationship between the identified genes and HNC. The validated top risk genes and their network-expanded neighbors were mapped against DrugBank, and through statistical significance testing, established significant drug-gene associations.

Significant genes associated with HNC, inferred by genomics alteration, were identified across HPV-positive and HPV-negative subgroups, such as PIK3CA, SOX2, TP53, EIF4G1, TLR7, CLDN1, PRKCI, and EPHA2. Further expansion through the PPI network identified other targetable genes such as EGFR, ERBB2, and the FGFRs. Literature based validation efforts ensured provided confidence in the gene-disease association. Drug-gene mapping revealed candidates spanning already in clinical trials for HNC (e.g. Afatinib, Cabozantinib, Dasatinib, Brigatinib, Lenvatinib, Capivasertib, Erdafitinib) and emerging or repurposing candidates (Amuvatinib, XL765 (Voxtalisib), Golotimod, Artenimol, Quercetin, and Acetylsalicylic Acid), offering opportunities for precision repurposing.

The GARD pipeline demonstrates a genomics-driven, network-informed framework for systematic drug repurposing in HNC. HPV stratification enhances precision, literature-based validation strengthens confidence, and integrated drug mapping enables refinement of existing therapies and discovery of novel candidates for personalized treatment strategies.

The full implementation of the GARD pipeline, including preprocessing scripts, statistical analysis modules, and visualization tools, is publicly available on GitHub at: https://github.com/pvtanike/Genomic-Landscape-Based-Drug-Repurposing.git.