title: Androgen-independent molecular imaging vectors to detect castration-resistant and metastatic prostate cancer.
abstract: Prostate-specific promoters are frequently employed in gene-mediated molecular imaging and therapeutic vectors to diagnose and treat castration-resistant prostate cancer (CRPC) that emerges from hormone ablation therapy. Many of the conventional prostate-specific promoters rely on the androgen axis to drive gene expression. However, considering the cancer heterogeneity and varying androgen receptor status, we herein evaluated the utility of prostate-specific enhancing sequence (PSES), an androgen-independent promoter in CRPC. The PSES is a fused enhancer derived from the prostate-specific antigen (PSA) and prostate-specific membrane antigen gene regulatory region. We augmented the activity of PSES by the two-step transcriptional amplification (TSTA) system to drive the expression of imaging reporter genes for either bioluminescent or positron emission tomography (PET) imaging. The engineered PSES-TSTA system exhibits greatly elevated transcriptional activity, androgen independency, and strong prostate specificity, verified in cell culture and preclinical animal experimentations. These advantageous features of PSES-TSTA elicit superior gene expression capability for CRPC in comparison with the androgen-dependent PSA promoter-driven system. In preclinical settings, we showed robust PET imaging capacity of PSES-TSTA in a castrated prostate xenograft model. Moreover, intravenous administrated PSES-TSTA bioluminescent vector correctly identified tibial bone marrow metastases in 9 of 9 animals, whereas NaF- and FDG-PET was unable to detect the lesions. Taken together, this study showed the promising utility of a potent, androgen-independent, and prostate cancer-specific expression system in directing gene-based molecular imaging in CRPC, even in the context of androgen deprivation therapy.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Ziyue Karen
authors.initials: ZK
authors.lastname: Jiang
authors.forename: Makoto
authors.initials: M
authors.lastname: Sato
authors.forename: Liu H
authors.initials: LH
authors.lastname: Wei
authors.forename: Chinghai
authors.initials: C
authors.lastname: Kao
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009919:Orchiectomy; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen / Q000032:analysis* / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D013977:Tibia / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D000728:Androgens; D017430:Prostate-Specific Antigen