Project Title: Low-dose erlotinib and mesalamine for prevention of colitis-associated colorectal cancer (CAC)

About This Grant

Colitis-associated colorectal cancer (CAC), a serious complication of inflammatory bowel disease (IBD), is more aggressive than sporadic or hereditary colorectal cancer and lacks effective prevention strategies. Erlotinib (ERL), an epidermal growth factor receptor (EGFR) inhibitor, reduces tumor multiplicity and dysplasia in preclinical CAC models by suppressing Wnt signaling and Mmp-7 expression. However, daily ERL dosing causes significant skin toxicity, highlighting the need for safer, intermittent dosing strategies. Mesalamine (5- ASA), an anti-inflammatory aminosalicylate and first-line ulcerative colitis (UC) treatment, offers modest CAC protection, likely via cyclooxygenase-2 (COX-2) and downstream prostaglandin E2 (PGE2) suppression. This proposal evaluates intermittent low-dose ERL, alone or combined with 5-ASA, to safely target both tumor epithelium and immune microenvironment. We hypothesize that dual targeting of EGFR and inflammatory pathways will suppress tumor progression and colitis while minimizing toxicity. Tumor-associated macrophages (TAMs), regulated by EGFR and PGE2, are a central mechanistic focus due to their role in CAC progression. Using the azoxymethane/dextran sodium sulfate (AOM/DSS) rat model, we will validate the model, profile pharmacodynamic (PD) biomarkers, define the optimal ERL and 5-ASA monotherapy doses through PD-guided short-term studies, and evaluate the long-term efficacy and toxicity of combined ERL+5-ASA treatment. The studies will assess TAM polarization, T cell infiltration, and inflammatory chemokines as mechanistic endpoints. Support is requested from the NCI PREVENT program to complete these PD-guided preclinical studies, structured per Task Order RFP guidelines, to inform future prevention trials in IBD patients.