Targeting MAO B: A novel gut–brain axis link in colorectal cancer progression.

Abstract

231 Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with recurrence and metastasis contributing significantly to poor outcomes. Recent studies have reported elevated expression levels of monoamine oxidases (MAO A and MAO B), enzymes that regulate neurotransmitter metabolism and gut–brain axis in CRC. While MAO A has been well studied, the role of MAO B in CRC is less understood. Our real-world data revealed that high MAO B expression in CRC correlates with poor prognosis and survival. Additionally, in Bevacizumab (Bev) treated patients when evaluating MAO B as a continuous variable, lower expression had significantly better overall survival (Cox LRT P = 0.015, covariate adjusted). Hence, we investigated the role of MAO B in CRC and its association with epithelial–mesenchymal transition (EMT) and angiogenesis. Methods: We established two CRC patient derived xenograft (PDX) models with high or low MAO B activity. We implanted patient’s tumor samples (F0 generation) with high MAO B activity (MAO high) or low MAO B activity (MAO low) subcutaneously in 6-8 weeks NSG mice (F1 generation). For each PDX model trial, F1 tumors were pooled and implanted in NSG mice (F2 generation). We evaluated MAO B inhibitor Deprenyl efficacy in comparison with vehicle group in MAO high and low PDX models. Downstream analysis was done using Immunohistochemistry (IHC) to assess metastatic and proliferation markers, and bulk RNA sequencing to characterize differentially expressed genes across treatment groups. We then evaluated the efficacy of MAO B inhibitors- Deprenyl, Rasagiline and Safinamide in CRC HT29 cell line-derived xenograft (CDX) model as monotherapies and in combination with Bev. Results: In the PDX model, Deprenyl significantly reduced the tumor volume as compared to vehicle group (p=0.0254) in MAO B high group but not in MAO B low group. IHC showed significant reduction in the expression of metastatic and tumor growth markers (Ki67, MMP9 and CD37) in the treatment group. RNA sequencing revealed significant upregulation of tumor suppressor and proapoptotic genes like MIR-3648, ENTPD8, RBM5 and ANO9 in Deprenyl treated group. In the HT29 CRC CDX model, all three MAO B inhibitors, Deprenyl, Rasagiline and Safinamide significantly reduced tumor volume when compared with vehicle control, with further tumor growth suppression observed when combined with Bev. Combination therapy also conferred a significant survival advantage compared to Bev alone, accompanied by downregulation of EMT and angiogenetic markers at the transcript level. Conclusions: MAO B represents a promising biomarker and therapeutic target in CRC. Pharmacologic inhibition of MAO B reduces tumor growth, angiogenesis, and metastatic potential, and enhances survival in preclinical models. These findings highlight the translational potential of MAO B inhibitors, warranting further investigation as novel therapeutic strategies for CRC.