Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer.

Lethal prostate cancer (PCa) is characterized by the presence of metastases and the development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. The goal of our study was to characterize the potential role of l-CaD in PCa metastases and antiandrogen therapy resistance. In this study, we extracted co-expression data of l-CaD from the largest public PCa patient data sets and identified the common transcripts between the sets. The common co-expression hits were used to recognize biological processes associated with l-CaD in the PCa context. Next, we used in vitro techniques, including 3D culture, cell viability assays, immunofluorescence staining, and Western blotting, to study the role of l-CaD in PCa with a focus on cancer hallmarks and the recognized associated biological processes. Finally, we used in vivo zebrafish and mouse xenograft models to verify the findings observed in silico in PCa patient data and in vitro in PC3, DU145, and VCaP cell lines. Here, we report that in vitro downregulation of l-CaD promotes the epithelial phenotype and reduces the spheroid growth in 3D, which is reflected in vivo in the reduced formation of metastases in a zebrafish PCa xenograft model. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets and that GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation. Citation Format: Verneri Virtanen, Kreetta Paunu, Antti Kukkula, Saana Niva, Ylva Junila, Mervi Toriseva, Terhi Jokilehto, Sari Mäkelä, Riikka Huhtaniemi, Matti Poutanen, Ilkka Paatero, Maria Sundvall. Glucocorticoid receptor-induced non-muscle caldesmon regulates growth and metastasis in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A024.