Evaluation of Tissue from Patients with Prostate Cancer Identifies B7-H3 as an Androgen-Regulated, Broadly-Expressed, Combinatorial Therapeutic Target.

PURPOSE: Advanced Prostate Cancer (PCa) management suffers from therapeutic resistance due to naturally transient or AR-dependent expression of clinically actionable surface targets. We aimed to identify the most promising clinically relevant PCa targets using RNA and protein expression levels across the PCa continuum-hormone-sensitive, castration-resistant, neuroendocrine, and "double-negative" prostate cancer (DNPC). EXPERIMENTAL DESIGN: We performed integration of a large single-cell transcriptomics atlas (JHU-PANORAMA, ~1 million cells and 213 patients) and PDX models for systematic investigation of clinically relevant surfaceome, followed by proteomic validation on patient samples and mechanistic investigations on PCa cell lines and patient samples. RESULTS: B7-H3 was found to be the most uniformly expressed across the entire PCa continuum. JHU-PANORAMA is made available for interactive visualization as RShiny webapp. Further mitigation of therapeutic resistance is proposed through a systematic framework for bispecific antibody design, where B7-H3 demonstrated high combinatorial scores with TROP-2, NECTIN1, KLK2, and NECTIN4. B7-H3 was also shown to be negatively regulated by AR and synergistically inhibited tumor growth when combined with androgen inhibition. CONCLUSIONS: B7-H3 demonstrates low inter-patient and intra-tumoral heterogeneity with significant synergistic effects in combination with AR inhibition. These properties could uniquely place B7-H3 as a broad-spectrum therapeutic target with the potential to combine B7-H3 based therapeutics with standard ADT for synergistic effects to overcome therapeutic resistance across the PCa disease continuum.