Proteogenomic Biomarker Profiling for Predicting Radiolabeled Immunotherapy Response in Resistant Prostate Cancer.

Abstract

Treatment resistance prevents patients with preoperative chemoradiotherapy or targeted radiolabeled immunotherapy from achieving a good result, which remains a major challenge in the prostate cancer (PCa) area. A novel integrative framework combining a machine learning workflow with proteogenomic profiling was used to identify predictive ultrasound biomarkers and classify patient response to radiolabeled immunotherapy in high-risk PCa patients who are treatment resistant. The deep stacked autoencoder (DSAE) model, combined with Extreme Gradient Boosting, was designed for feature refinement and classification. The Cancer Genome Atlas and an independent radiotherapy-treated cohort have been utilized to collect multiomics data through their respective applications. In addition to genetic mutations (whole-exome sequencing), these data contained proteomic (mass spectrometry) and transcriptomic (RNA sequencing) data. Maintaining biological variety across omics layers while reducing the dimensionality of the data requires the use of the DSAE architecture. Resistance phenotypes show a notable relationship with proteogenomic profiles, including DNA repair pathways (Breast Cancer gene 2 [BRCA2], ataxia-telangiectasia mutated [ATM]), androgen receptor (AR) signaling regulators, and metabolic enzymes (ATP citrate lyase [ACLY], isocitrate dehydrogenase 1 [IDH1]). A specific panel of ultrasound biomarkers has been confirmed in a state deemed preclinical using patient-derived xenografts. To support clinical translation, real-time phenotypic features from ultrasound imaging (e.g., perfusion, stiffness) were also considered, providing complementary insights into the tumor microenvironment and treatment responsiveness. This approach provides an integrated platform that offers a clinically actionable foundation for the development of radiolabeled immunotherapy drugs before surgical operations.