Abstract 4671: MAO A, MAO B inhibitors and NMI for colon cancer therapy

Background: Mitochondrial MAO A and MAO B isoenzymes catalyze oxidative deamination of neuroactive and vasoactive monoamines in CNS and peripheral tissues. MAO A inhibitors have been used as antidepressants; MAO B inhibitors have been used for Parkinson’s disease. Recently, we and others have shown MAO inhibitors can be repurposed for cancer therapy. This study focused on the MAO inhibitors as a novel therapeutic strategy for CRC utilizing patient derived xenograft (PDX) platform which recapitulates the patient’s molecular characteristics. Methods and Results: CRC PDX models were selected from our repository based on MAO A and B expression and activity. To establish two PDX models with high or low MAO A/B activity we implanted patient’s tumor samples (F0 generation) with high MAO A/B activity (MAO high) or low MAO A/B activity (MAO low) in 8 weeks NSG mice (F1 generation). F1 MAO low PDX model showed substantially slower tumor growth rates as compared to MAO high PDX model (200 days vs 65 days), suggesting the role of MAOs in CRC growth. For each PDX model trial, tumors were pooled from 6 F1 PDX mice and implanted in 30 NSG mice (F2 generation). There were five mice in each of experimental groups: one control arm (vehicle: 67% PEG 400, 33% saline) and treatment arms (i.p. for 21 days): 1. MAO A inhibitors: clorygyline: 50mg/kg; 2. Near infrared dye conjugated MAO A inhibitor (NMI): 5 mg/kg; 3. MAO B inhibitor: deprenyl 10mg/kg;4. MAO A & B inhibitor: phenelzine (30mg/kg). MAO high PDX cohort showed significant reduction in tumor volume in mice treated with MAO A inhibitors clorygyline (p=0.009); NMI (p=0.053) and MAO B inhibitor deprenyl (p=0.022), phenelzine (p= 0.097) when compared to control. Angiogenesis marker CD31 staining of tumor tissues showed significant reduction in mice treated with clorygyline and NMI. Additionally, Ki 67 staining demonstrated considerable decrease in cell proliferation and TUNEL assay exhibited increase in apoptosis in tumor treated with clorygyline and NMI. RNA sequencing revealed 50 differentially expressed genes (DEGs) between clorygyline treated tumors and control, 171 between NMI treated and control group (padj =1.5). Ingenuity Pathway Analysis showed alterations in pathways including oxidative phosphorylation, sirtuin pathway, estrogen receptor signaling, and mitochondrial dysfunction. NMI showed same efficacy with no toxicity compared to clorygyline even at 10 times lower dose in MAO high PDX mode