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Cancers
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Recent Scientific Developments in Metastatic Prostate Cancer
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Recent Scientific Developments in Metastatic Prostate Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 23343

Special Issue Editor

Dr. Isabel Heidegger-Pircher

E-Mail Website
Guest Editor
Department of Urology, Medical University Innsbruck, 6020 Innsbruck, Austria
Interests: metastatic prostate cancer; hormonal therapy; chemotherapy; immunotherapy; PARP inhibition; combination therapies; emerging (pre)clinical mCRPC treatment options; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The treatment of metastatic prostate cancer (mPCa) has substantially changed in recent years. While some years ago, androgen deprivation therapy (ADT) was the standard therapy for PCa, we are now confronted with therapeutic options like chemotherapies, second-generation ADTs, or radium 223. In addition, we have promising data on the use of PARP inhibitors, immunotherapeutic agents, or PSMA lutetium.

Beside monotherapies, combination therapies are currently being evaluated to further improve clinical efficacy. Moreover, some other promising new treatment options have demonstrated preclinical efficacy and are currently in the early phases of clinical trials.

One of the biggest challenges to progress is the definition of biomarkers that allow selection of the appropriate therapy for each patient in order to pursue a personalized treatment approach.

This Special Issue of Cancers therefore encompasses new research articles and timely reviews on 1) emerging treatment options in mCRPC (preclinical and clinical) as well as on 2) biomarkers predicting response to mCRPC therapies.

Dr. Isabel Heidegger-Pircher
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metastatic prostate cancer
  • hormonal therapy
  • chemotherapy
  • immunotherapy
  • PARP inhibition
  • combination therapies
  • emerging (pre)clinical mCRPC treatment options
  • biomarkers

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Published Papers (7 papers)

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Editorial

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2 pages, 139 KiB  
Editorial
Recent Scientific Developments in Metastatic Prostate Cancer
by Isabel Heidegger
Cancers 2020, 12(11), 3280; https://doi.org/10.3390/cancers12113280 - 6 Nov 2020
Cited by 1 | Viewed by 1516
Abstract
In recent years, the treatment landscape of advanced prostate cancer has radically changed [...] Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)

Research

Jump to: Editorial

17 pages, 5690 KiB  
Article
Organ-Specific Uptake of Extracellular Vesicles Secreted by Urological Cancer Cells
by Johannes Linxweiler, Anja Kolbinger, Dirk Himbert, Philip Zeuschner, Matthias Saar, Michael Stöckle and Kerstin Junker
Cancers 2021, 13(19), 4937; https://doi.org/10.3390/cancers13194937 - 30 Sep 2021
Cited by 10 | Viewed by 2261
Abstract
Extracellular vesicles (EVs) secreted by cancer cells have been shown to take a pivotal part in the process of local and systemic tumor progression by promoting the formation of a supportive local tumor microenvironment and preparing premetastatic niches in distant organ systems. In [...] Read more.
Extracellular vesicles (EVs) secreted by cancer cells have been shown to take a pivotal part in the process of local and systemic tumor progression by promoting the formation of a supportive local tumor microenvironment and preparing premetastatic niches in distant organ systems. In this study, we analyzed the organ-specific uptake of EVs secreted by urological cancer cells using an innovative in-vivo approach. EVs from benign and malignant prostate, kidney, and bladder cells were isolated using ultracentrifugation, fluorescence-labeled and injected intravenously in immunodeficient mice. After 12 or 24 h, the animals were sacrificed, their organs were harvested and analyzed for the presence of EVs by high-resolution fluorescence microscopy. Across all entities, EVs were taken up fast (12 h > 24 h), and EVs from malignant cells were taken up more efficiently than EVs from benign cells. Though not entirely organ-specific, EVs were incorporated in different amounts, depending on the entity (prostate: lung > liver > brain; kidney: brain > lung > liver; bladder: lung > liver > brain). EV uptake in other organs than lung, liver, brain, and spleen was not observed. Our results suggest a role of EVs in the formation of premetastatic niches and an organotropism in EV uptake, which have to be examined in more detail in further studies. Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
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23 pages, 7264 KiB  
Article
Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis
by Sascha D. Markowitsch, Kira M. Juetter, Patricia Schupp, Kristine Hauschulte, Olesya Vakhrusheva, Kimberly Sue Slade, Anita Thomas, Igor Tsaur, Jindrich Cinatl, Jr., Martin Michaelis, Thomas Efferth, Axel Haferkamp and Eva Juengel
Cancers 2021, 13(4), 882; https://doi.org/10.3390/cancers13040882 - 20 Feb 2021
Cited by 44 | Viewed by 4004
Abstract
The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, [...] Read more.
The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, the parental (=sensitive) and docetaxel (DX)-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1–1.5 μM], and tumor cell growth, proliferation, cell cycling, cell death (apoptosis, necrosis, and necroptosis), and metabolic activity were evaluated. Correspondingly, the expression of regulating proteins was assessed. Exposure to SHI time- and dose-dependently inhibited tumor cell growth and proliferation in parental and DX-resistant PCa cells, accompanied by cell cycle arrest in the G2/M or S phase and modulation of cell cycle regulating proteins. SHI induced apoptosis and more dominantly necroptosis in both parental and DX-resistant PCa cells. This was shown by enhanced pRIP1 and pRIP3 expression and returned growth if applying the necroptosis inhibitor necrostatin-1. No SHI-induced alteration in metabolic activity of the PCa cells was detected. The significant antitumor effects induced by SHI to parental and DX-resistant PCa cells make the addition of SHI to standard therapy a promising treatment strategy for patients with advanced PCa. Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
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Graphical abstract

16 pages, 2173 KiB  
Article
The Prognostic Role of Baseline Metabolic Tumor Burden and Systemic Inflammation Biomarkers in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Radium-223: A Proof of Concept Study
by Matteo Bauckneht, Sara Elena Rebuzzi, Alessio Signori, Maria Isabella Donegani, Veronica Murianni, Alberto Miceli, Roberto Borea, Stefano Raffa, Alessandra Damassi, Marta Ponzano, Fabio Catalano, Valentino Martelli, Cecilia Marini, Francesco Boccardo, Silvia Morbelli, Gianmario Sambuceti and Giuseppe Fornarini
Cancers 2020, 12(11), 3213; https://doi.org/10.3390/cancers12113213 - 31 Oct 2020
Cited by 25 | Viewed by 2863
Abstract
Over the last years has emerged the urgent need for the identification of reliable prognostic biomarkers able to potentially identify metastatic castration-resistant prostate cancer (mCRPC) patients most likely to benefit from Radium-223 (Ra-223) since baseline. In the present monocentric retrospective study, we analyzed [...] Read more.
Over the last years has emerged the urgent need for the identification of reliable prognostic biomarkers able to potentially identify metastatic castration-resistant prostate cancer (mCRPC) patients most likely to benefit from Radium-223 (Ra-223) since baseline. In the present monocentric retrospective study, we analyzed the prognostic power of systemic inflammation biomarkers and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET)-derived parameters and their potential interplay in this clinical setting. The following baseline laboratory parameters were collected in 59 mCRPC patients treated with Ra-223: neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelets-to-lymphocyte ratio (PLR), and systemic inflammation index (SII), while maximum Standardized Uptake Value, Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) were calculated in the 48 of them submitted to baseline FDG-PET. At the univariate analysis, NLR, dNLR, MTV, and TLG were able to predict the overall survival (OS). However, only NLR and MTV were independent predictors of OS at the multivariate analysis. Additionally, the occurrence of both increased NLR and MTV at baseline identified mCRPC patients at higher risk for lower long-term survival after treatment with Ra-223. In conclusion, the degree of systemic inflammation, the quantification of the metabolically active tumor burden and their combination might represent potentially valuable tools for identifying mCRPC patients who are most likely to benefit from Ra-223. However, further studies are needed to reproduce these findings in larger settings. Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
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15 pages, 3101 KiB  
Article
Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients
by Paul König, Markus Eckstein, Rudolf Jung, Amer Abdulrahman, Juan Guzman, Katrin Weigelt, Ginette Serrero, Jun Hayashi, Carol Geppert, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Sven Wach, Helge Taubert and Verena Lieb
Cancers 2020, 12(9), 2639; https://doi.org/10.3390/cancers12092639 - 16 Sep 2020
Cited by 7 | Viewed by 3086
Abstract
Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa [...] Read more.
Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa tumors. The aim of this study was to characterize the protein expression of the AR and its splice variant, AR-V7, and their subcellular distributions in PCa by immunohistochemistry and to correlate the results to the clinicopathological data and prognosis. Immunohistochemical staining for AR and AR-V7 was performed on a tissue microarray (TMA) with specimens from 410 PCa patients using an immunoreactive score (IRS) or only the percentage of AR-V7 staining in cytoplasmic granules. Nuclear or cytoplasmic AR staining was not associated with prognosis. AR-V7 staining was only occasionally observed in the nucleus. However, AR-V7 staining in the cytoplasm or in cytoplasmic granules was associated with relapse-free survival (RFS). AR-V7 staining of the cytoplasm was associated with a shorter RFS, whereas AR-V7 staining of cytoplasmic granules was associated with a longer RFS. In a multivariate Cox’s regression analysis, only negative (<5%) AR-V7 staining of cytoplasmic granules remained an independent prognostic factor for RFS (HR = 5.3; p = 0.006). In a further subgroup analysis by multivariate Cox’s regression analysis, AR-V7 was an independent prognostic factor in the following groups: age ≤ 65 (HR = 9.7; p = 0.029), negative CK20 staining (HR = 7.0; p = 0.008), and positive perineural invasion (HR = 3.7; p = 0.034). Altogether, AR-V7 protein in granular cytoplasmic structures is an independent prognostic factor for RFS in PCa patients. Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
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14 pages, 875 KiB  
Article
Oncological Outcomes of Metastasis-Directed Therapy in Oligorecurrent Prostate Cancer Patients Following Radical Prostatectomy
by Gaëtan Devos, Charlien Berghen, Henri Van Eecke, Arthur Vander Stichele, Hendrik Van Poppel, Karolien Goffin, Cindy Mai, Liesbeth De Wever, Maarten Albersen, Wouter Everaerts, Gert De Meerleer and Steven Joniau
Cancers 2020, 12(8), 2271; https://doi.org/10.3390/cancers12082271 - 13 Aug 2020
Cited by 20 | Viewed by 3695
Abstract
Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of [...] Read more.
Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ≤5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan–Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27–70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58–164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103–132). In total, 314 MDTs were performed and 25 patients (13%) received ≥3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials. Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
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18 pages, 2646 KiB  
Article
Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer
by Mona Kafka, Fabian Mayr, Veronika Temml, Gabriele Möller, Jerzy Adamski, Julia Höfer, Stefan Schwaiger, Isabel Heidegger, Barbara Matuszczak, Daniela Schuster, Helmut Klocker, Jasmin Bektic, Hermann Stuppner and Iris E. Eder
Cancers 2020, 12(8), 2092; https://doi.org/10.3390/cancers12082092 - 28 Jul 2020
Cited by 15 | Viewed by 4953
Abstract
The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration [...] Read more.
The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance. Full article
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
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