[Therapy sequences and duration in mCRPC: a retrospective review of the Lübeck mCRPC cohort]. / Therapiesequenzen und ­dauer beim mCRPC: Eine retrospektive Aufarbeitung der Lübecker mCRPC-Kohorte.

BACKGROUND: Prostate cancer is one of the most common cancers in men in Europe. Several classes of agents can be considered for the treatment of metastatic prostate carcinoma, and their use is supported by extensive guidelines. In the treatment of metastatic castration-resistant prostate cancer (mCRPC), it is currently unclear which sequence of systemic therapies is most effective. Currently approved system therapies in the castration-resistant setting generally include hormone-manipulating agents, taxane-based chemotherapies, radioactive agents, or inhibitiors of DNA repair mechanisms. This study aims to summarize real world data of mCRPC therapy. METHODS: Retrospectively, 90 mCRPC patients undergoing treatment at the University Hospital Schleswig-Holstein, Lübeck Campus between February 2006 and March 2020 were identified. The patient data were analyzed for their treatment sequence and disease progression. Due to the inclusion period, the mCRPC therapy sequences studied were limited to: Abiraterone, Cabazitaxel, Docetaxel, Enzalutamide, Lutetium-177-PSMA and Radium-223. The analysis includes the therapy sequences and their duration, clinical information of the respective cohort, overall and cancer-specific survival (OS/CSS) as well as time to second-line therapy in relation to the respective first-line therapy. RESULTS: Approximately two-thirds of patients underwent a true therapy sequence (at least two of the drugs listed above), with this proportion halving by the third line.The majority of patients received the sequence (first/second line) abiraterone/docetaxel (n=13), followed by docetaxel/abiraterone (n=12) and abiraterone/enzalutamid (n=10) and docetaxel/docetaxel (n=8).Within the different docetaxel sequences, first-line (mean 4.7 months ± SD 3.1; median 4.0) and rechallenge (mean 5.3 months ± SD 5.9; median 3.0) therapy durations were the longest. The subjective side effect rate of docetaxel was lower in the second line, so that a better tolerability can be assumed here.The abiraterone/docetaxel sequence was used mainly in patients with metachronous metastases. Among the different sequences of abiraterone, first-line (mean 10.8 months ± SD 10.2; median 9.0) and second-line (mean 10.6 months ± SD 9.0; median 7.0) therapy durations were the longest.The sequence abiraterone/enzalutamide was prescribed mainly to older patients with synchronous metastases. Among the different enzalutamide sequences first-line (mean 9.6 months ± SD 7.1; median 7.0) and rechallenge (mean 11.0 ± SD 0.0; median 11.0) therapy durations were the longest.In contrast, the sequence docetaxel/docetaxel was used mainly in younger patients with a high initial PSA.The evaluation shows a trend that both abiraterone and enzalutamide can account for a survival advantage in the first line. CONCLUSION: Ultimately, an optimal treatment sequence cannot be confidently derived from these data.However, it was found that only a small proportion of patients underwent fourth- or even fifth-line treatment at all. Thus, the focus on first- and second-line in this study seems reasonable. It could be shown in a trend that docetaxel as first-line therapy seems to be disadvantegous regarding OS as well as CSS when compared to abiraterone or enzalutamide. However, due to the small number of patients in this study, a clear significance cannot be derived. Moreover, the subjectively better tolerability of docetaxel in the second-line setting could provide an impetus for treatment planning in multimorbid elderly patients in the future. The sequence abiraterone/docetaxel may offer a beneficial option for initial mCRPC therapy.

CEACAM6 Promotes Lung Metastasis via Enhancing Proliferation, Migration and Suppressing Apoptosis of Prostate Cancer Cells.

BACKGROUND/AIM: Metastatic prostate cancer (mPCa) results in high morbidity and mortality. Visceral metastases in particular are associated with a shortened survival. Our aim was to unravel the molecular mechanisms that underly pulmonary spread in mPCa. MATERIALS AND METHODS: We performed a comprehensive transcriptomic analysis of PCa lung metastases, followed by functional validation of candidate genes. Digital gene expression analysis utilizing the NanoString technology was performed on mRNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissue from PCa lung metastases. The gene expression data from primary PCa and PCa lung metastases were compared, and several publicly available bioinformatic analysis tools were used to annotate and validate the data. RESULTS: In PCa lung metastases, 234 genes were considerably up-regulated, and 78 genes were significantly down-regulated when compared to primary PCa. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) was identified as suitable candidate gene for further functional validation. CEACAM6 as a cell adhesion molecule has been implicated in promoting metastatic disease in several solid tumors, such as colorectal or gastric cancer. We showed that siRNA knockdown of CEACAM6 in PC-3 and LNCaP cells resulted in decreased cell viability and migration as well as enhanced apoptosis. Comprehensive transcriptomic analyses identified several genes of interest that might promote metastatic spread to the lung. CONCLUSION: Functional validation revealed that CEACAM6 might play an important role in fostering metastatic spread to the lung of PCa patients via enhancing proliferation, migration and suppressing apoptosis in PC-3 and LNCaP cells. CEACAM6 might pose an attractive therapeutic target to prevent metastatic disease.

Comprehensive transcriptomic analysis of prostate cancer lung metastases.

Metastatic prostate cancer (mPCa) is a widespread disease with high mortality. Unraveling molecular mechanisms of disease progression is of utmost importance. The microenvironment in visceral organs and the skeletal system is of particular interest as a harbinger of metastatic spread. Therefore, we performed a comprehensive transcriptomic analysis of prostate cancer lung metastases with a special focus on differentially expressed genes attributable to the microenvironment. Digital gene expression analysis using the NanoString nCounter analysis system was performed on formalin-fixed, paraffin-embedded (FFPE) tissue from prostate cancer (PCa) lung metastases (n = 24). Data were compared to gene expression data from primary PCa and PCa bone metastases. Bioinformatic analysis was performed using several publicly available tools. In comparison to prostate cancer bone metastases, 209 genes were significantly upregulated, and 100 genes were significantly downregulated in prostate cancer lung metastases. Among the up-regulated genes, the top 10 genes with the most significant P-value were HLA-DPB1, PTPRC, ITGB7, C3, CCL21, CCL5, ITGAM, SERPINA1, MFAP4, ARAP2 and among the down-regulated genes, the top 10 genes with the most significant P-value were FOXC2, TWIST1, CDK14, CHAD, IBSP, EPN3, VIT, HAPLN1, SLC44A4, TBX1. In PCa lung metastases genes associated with immunogenic responses were upregulated while genes associated with epithelial-mesenchymal transition were down-regulated. We also showed that CXCR3/CXCL10 axis plays a significant role in prostate cancer lung metastases in comparison to bone metastases. In this study, we comprehensively explored transcriptomic alterations in PCa lung metastases in comparison to primary PCa and PCa bone metastases. In PCa lung metastases genes associated with immunogenic responses are upregulated while genes associated with epithelial-mesenchymal transition are down-regulated. This points to a more immunogenic phenotype of PCa lung metastases thus potentially making patients more susceptible to immunotherapeutic approaches.

ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription.

Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.

Proteomic analysis of the urothelial cancer landscape.

Urothelial bladder cancer (UC) has a wide tumor biological spectrum with challenging prognostic stratification and relevant therapy-associated morbidity. Most molecular classifications relate only indirectly to the therapeutically relevant protein level. We improve the pre-analytics of clinical samples for proteome analyses and characterize a cohort of 434 samples with 242 tumors and 192 paired normal mucosae covering the full range of UC. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify robust proteomic subtypes with prognostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both in silico and in vitro data indicate predictive value of the proteomic clusters for these drugs. We underline that proteomics is relevant for personalized oncology and provide abundance and tumor specificity data for a large part of the UC proteome ( www.cancerproteins.org ).