B7-H3 as a Therapeutic Target in Advanced Prostate Cancer

• DOI: 10.1016/j.eururo.2022.09.004
• Publication Date: 2022-09-13T12:54:33Z
• Authors: Christina Guo; Ines Figueiredo; Bora Gurel; Antje Neeb; George Seed; Mateus Crespo; Suzanne Carreira; Jan Rekowski; Lorenzo Buroni; Jon Welti; Denisa Bogdan; Lewis Gallagher; Adam Sharp; Maria D. Fenor de...; Pasquale Rescigno; Daniel Westaby; Khobe Chandran; Ruth Riisnaes; Ana Ferreira; Susana Miranda; Bianca Calì; Andrea Alimonti; Silvia Bressan; Alana H.T. Nguyen; Michael M. Shen; Jessica E. Hawley; Aleksandar Obradovic; Charles G. Drake; Claudia Bertan; Chloe Baker; Nina Tunariu; Wei Yuan; Johann S. de Bono
• Keywords: Male; 0301 basic medicine; Biopsy; Antineoplastic Agents; Adenocarcinoma; 3. Good health; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; Receptors, Androgen; Cell Line, Tumor; Humans; Transcriptome; Signal Transduction; Transcription Factors

B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development patient selection for targeted therapies.To characterise same-patient hormone-sensitive (HSPC) castration-resistant (CRPC) PC biopsies, associating this genomics, evaluate antitumour activity an anti-B7-H3 antibody-drug conjugate (ADC) human CRPC vitro vivo.We performed immunohistochemistry next-generation sequencing on cohort 98 clinically annotated including 72 patients who also had HSPC biopsies analyses. We analysed two transcriptome exome datasets, scRNASeq datasets. organoids (patient-derived xenograft [PDX]-derived [PDX-Os]) were derived from PDXs generated biopsies.We evaluated mRNA relation panel 770 immune-related genes, compared protein between determined associations genomic alterations, DS-7300a, topoisomerase-1 inhibitor payload ADC, lines, (PDX-Os), xenografts (PDXs) different histologies, expressions, genomics.B7-H3 was among most highly expressed genes CRPCs. Most CRPCs (93%) B7-H3, developed CRPC, frequently time diagnosis (97%). Conversion positive negative, or vice versa, during progression uncommon. neuroendocrine features more likely be negative (28%) than adenocarcinomas. tumours defective DNA repair gene (ATM BRCA2) alterations associated ERG expression, androgen receptor (AR) AR signature. DS7300a against expressing models PDX-Os, adenocarcinoma histology.The frequent overexpression normal tissue other B7 family members implicates it as relevant therapeutic target these diseases. Mechanisms driving differences across subsets warrant investigation understanding role cancer growth clinical therapies.B7-H3, lethal cancers, particular those specific mutations, can using drugs that bind B7-H3. These findings such deciding which treat new drugs.