Abstract B025: Integrated proteomic and molecular profiling reveals race-associated RNA splicing and metabolic reprogramming in prostate cancer

Abstract Background: Prostate cancer (PCa) disproportionately affects African American (AA) men, who experience higher incidence, earlier onset, and poorer outcomes than Caucasian (CA) men. The molecular mechanisms underlying these disparities remain poorly understood. This study uniquely integrates proteomic, molecular, and bioinformatics analyses to uncover race-specific protein expression patterns and biological pathways driving aggressive and therapy-resistant PCa. Methods: Clinical samples (n = 28) were collected from AA (n = 10) and CA (n = 10) PCa patients. For each group, four healthy control prostate tissues were also collected. We conducted an integrated LC-MS-based proteomic analysis of patient tissues to investigate race-specific differential protein expression. Multivariate statistical modeling (OPLS-DA, hierarchical clustering) was used to identify race-distinct protein signatures. Key targets were validated by Western blotting and qPCR in AA-derived MDA-PCa-2B, CA-derived PC-3 cell lines, C4-2B cells, and VCaP cells. Functional annotation and pathway enrichment analyses were performed to assess biological significance. Tissue immunohistochemistry (IHC) and Raman lipid mapping further evaluated the expression of key protein markers (AR, PSA, PSMA, CAV1) and lipid species, including ω-3, ω-6 fatty acids and cholesterol. Results: Distinct molecular profiles emerged between AA and CA tumors. AA tissues and MDA-PCa-2B cells exhibited marked upregulation of the splicing regulators SRSF9 and HNRNPH3, metabolic enzyme MCCC2, surface antigen FOLH1 (PSMA), and ferritin subunits (FTH1/FTL). Gene ontology and pathway analyses highlighted enrichment in RNA splicing (notably AR-V7 variant production), mTOR/PI3K-AKT signaling, amino acid and folate metabolism, and iron homeostasis. The recently established role of SRSF9 in promoting AR-V7 formation suggests a splicing-based mechanism of androgen receptor (AR) reactivation and antiandrogen resistance in AA PCa. Raman lipid mapping further revealed enrichment of pro-tumorigenic lipid species (DHA, ALA, ω-6) and elevated cholesterol in AA tumors, aligning with IHC findings of increased AR and PSMA expression. Together, these alterations reflect a convergent network of metabolic and signaling adaptations underlying a therapy-resistant phenotype in AA PCa. Conclusion: This first integrated proteomic and lipidomic study in a race-stratified PCa cohort reveals molecular drivers of aggressive, therapy-resistant AA PCa. Upregulation of SRSF9, MCCC2, FOLH1, and ferritin, along with AR-V7–associated pathways and lipid remodeling, identifies novel targets for precision therapy. These findings provide critical insight into the biological basis of racial disparities in PCa outcomes. Citation Format: Praveen Kumar Guttula, Ganesan Muthusamy, Kirti Agrawal, Sanjit Roy, Shang Su, Nrusingh C Biswal, Hem D Shukla, Manas Ranjan Gartia. Integrated proteomic and molecular profiling reveals race-associated RNA splicing and metabolic reprogramming in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B025.