<h3>Objectives:</h3> Here we investigate a novel phosphodiesterase 10 (PDE10) inhibitor, MCI-030, as a drug candidate for the treatment or prevention of epithelial ovarian cancer (EOC). Prior research showed that MCI-030 decreased cancer incidence in the egg laying hen spontaneous model of EOC by a novel mechanism involving dual suppression of Wnt and MAPK signaling. This study aims to further understand the molecular pathways affected by MCI-030 in preventing EOC development. <h3>Methods:</h3> Hens were treated with MCI-030 or control feed for 6 months. Necropsy was then performed to assess tumor development. Total RNA from ovarian tissue of 8 MCI-030-treated hens (4 tumor, 4 normal) and 8 control hens (4 tumor, 4 normal) was isolated and analyzed for differential gene expression using RNA sequencing (RNAseq). RNAseq was performed by paired-end 75bp sequencing with ~35 million reads coverage using the Illumina NextSeq500 platform. Genes were mapped to the Gallus[gp1] GRCg6 reference genome. Differential gene expression analysis was performed using DESeq2; pathways were investigated in the Molecular Signatures Database of the GSEA (www.gsea-msigdb.org). <h3>Results:</h3> Tumors from MCI-030 treated hens had 1,412 significantly downregulated genes (fold-change≤-2.0; p<0.05) compared to control tumors, including genes in the Wnt and MAPK signaling pathways. The most significant downregulation was in the cytokinecytokine receptor interaction gene pathway (67 genes,p=3.18 e-37). Many pathways downregulated by MCI-030, e.g. PDE10A inhibition, corresponded with pathways upregulated in PDE10A high-expressing ovarian tumors in the TCGA (Figure1). As expected for typical ovarian tumor expression profiling, various immune and inflammatory pathways were upregulated in ovary tumors compared to normal ovaries of control hens. However, these were strikingly absent when comparing tumors vs. normal ovaries of MCI-030 treated hens. The gene expression profiles comparing normal ovaries of treated vs. untreated hens revealed only 22 differentially expressed genes. <h3>Conclusions:</h3> Our data show multiple gene pathways downregulated in tumors treated with MCI-030 compared to untreated controls, including pathways such as Wnt and MAPK believed to be suppressed by PDE10 inhibition. Interestingly, many of the MCI-030 downregulated pathways mirror those observed for genes whose expression was positively correlated PDE10A mRNA in ovarian tumors of The Cancer Genome Atlas (TCGA). Our data also suggest that MCI-030 might have minimum effect in normal ovaries, but in contrast ameliorates inflammation usually associated to the tumor microenvironment.