Evaluation of tissue from patients with prostate cancer identifies B7-H3 as an androgen-regulated, broadly-expressed, combinatorial therapeutic target

Abstract

Advanced prostate cancer management suffers from therapeutic resistance due to naturally transient or androgen receptor (AR)–dependent expression of clinically actionable surface targets. We aimed to identify the most promising clinically relevant prostate cancer targets using RNA and protein expression levels across the prostate cancer continuum—hormone-sensitive, castration-resistant, neuroendocrine, and “double-negative” prostate cancer. Experimental Design: We performed integration of a large single-cell transcriptomics atlas (JHU-PANORAMA, ∼1 million cells and 213 patients) and patient-derived xenograft models for the systematic investigation of the clinically relevant surfaceome, followed by proteomic validation on patient samples and mechanistic investigations on prostate cancer cell lines and patient samples. Results: B7 homolog 3 (B7-H3) was found to be the most uniformly expressed across the entire prostate cancer continuum. JHU-PANORAMA is made available for interactive visualization as an R Shiny web app. Further mitigation of therapeutic resistance is proposed through a systematic framework for bispecific antibody design, in which B7-H3 demonstrates high combinatorial scores with TROP-2, NECTIN1, KLK2, and NECTIN4. B7-H3 was also shown to be negatively regulated by AR and synergistically inhibit tumor growth when combined with androgen inhibition. Conclusions: B7-H3 demonstrates low interpatient and intratumoral heterogeneity, with significant synergistic effects in combination with AR inhibition. These properties could uniquely position B7-H3 as a broad-spectrum therapeutic target, with the potential to combine B7-H3 based therapeutics with standard androgen deprivation therapy for synergistic effects to overcome therapeutic resistance across the prostate cancer disease continuum.