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New Advances in Metastatic Prostate Cancer
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New Advances in Metastatic Prostate Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 20053

Special Issue Editor

Prof. Dr. Christian Thomas

E-Mail Website
Guest Editor
Department of Urology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
Interests: genitourinary cancers; biomarkers; resistance mechanisms; targeted therapy

Special Issue Information

Dear Colleagues,

The treatment of metastatic prostate cancer has evolved enormously within the last decade. The outcome data of recent clinical trials are encouraging in that prognosis of metastatic prostate cancer can been shifted from a life-threatening to chronic disease. However, novel resistance mechanisms complicate tumor control in advanced stages. In particular, treatment-related anaplastic tumors with neuroendocrine features pose a challenge for urooncologists.

Therefore, it is of major importance to explore the genetic alterations leading to treatment resistance and to seek out potential targets for specific treatment to regain tumor control.

In this Special Issue, experts in this field will review the current approaches to the management of patients with metastatic prostate cancer.

Prof. Dr. Christian Thomas
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

  • prostate cancer
  • imaging
  • biomarkers
  • systemic treatment
  • local treatment
  • resistance mechanism

Published Papers (7 papers)

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Research

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12 pages, 903 KiB  
Article
Oligometastatic Prostate Cancer: A Comparison between Multimodality Treatment vs. Androgen Deprivation Therapy Alone
by Francesco A. Mistretta, Stefano Luzzago, Andrea Conti, Elena Verri, Giulia Marvaso, Claudia Collà Ruvolo, Michele Catellani, Ettore Di Trapani, Gabriele Cozzi, Roberto Bianchi, Matteo Ferro, Giovanni Cordima, Antonio Brescia, Maria Cossu Rocca, Vincenzo Mirone, Barbara A. Jereczek-Fossa, Franco Nolè, Ottavio de Cobelli and Gennaro Musi
Cancers 2022, 14(9), 2313; https://doi.org/10.3390/cancers14092313 - 6 May 2022
Cited by 2 | Viewed by 1857
Abstract
Background: We compared multimodality treatment (MMT, defined as robot-assisted radical prostatectomy (RARP) with androgen deprivation therapy (ADT), with or without adjuvant radiotherapy (RT)) vs. ADT alone in oligometastatic prostate cancer (OPC) patients. Methods: From 2010 to 2018, we identified 74 patients affected by [...] Read more.
Background: We compared multimodality treatment (MMT, defined as robot-assisted radical prostatectomy (RARP) with androgen deprivation therapy (ADT), with or without adjuvant radiotherapy (RT)) vs. ADT alone in oligometastatic prostate cancer (OPC) patients. Methods: From 2010 to 2018, we identified 74 patients affected by cM1a-b OPC (≤5 metastases). Kaplan–Meier (KM) plots depicted cancer-specific mortality (CSM), disease progression, metastatic castration-resistant PC (mCRPC), and time to second-line systemic therapy rates. Multivariable Cox regression models (MCRMs) focused on disease progression and mCRPC. Results: Forty (54.0%) MMT and thirty-four (46.0%) ADT patients were identified. On KM plots, higher CSM (5.9 vs. 37.1%; p = 0.02), mCRPC (24.0 vs. 62.5%; p < 0.01), and second-line systemic therapy (33.3 vs. 62.5%; p < 0.01) rates were recorded in the ADT group. No statistically significant difference was recorded for disease progression. ForMCRMs adjusted for the metastatic site and PSA, a higher mCRPC rate was recorded in the ADT group. No statistically significant difference was recorded for disease progression. Treatment-related adverse events occurred in 5 (12.5%) MMT vs. 15 (44.1%) ADT patients (p < 0.01). Conclusions: MMT was associated with lower CSM, mCRPC, and second-line therapy rates. A lower rate of treatment-related adverse events was recorded for the MMT group. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
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14 pages, 2007 KiB  
Article
Local Control after Locally Ablative, Image-Guided Radiotherapy of Oligometastases Identified by Gallium-68-PSMA-Positron Emission Tomography in Castration-Sensitive Prostate Cancer Patients (OLI-P)
by Tobias Hölscher, Michael Baumann, Jörg Kotzerke, Klaus Zöphel, Frank Paulsen, Arndt-Christian Müller, Daniel Zips, Christian Thomas, Manfred Wirth, Esther G. C. Troost, Mechthild Krause, Steffen Löck and Fabian Lohaus
Cancers 2022, 14(9), 2073; https://doi.org/10.3390/cancers14092073 - 21 Apr 2022
Cited by 6 | Viewed by 2193
Abstract
Progression of prostate-specific antigen (PSA) values after curative treatment of prostate cancer patients is common. Prostate-specific membrane antigen (PSMA-) PET imaging can identify patients with metachronous oligometastatic disease even at low PSA levels. Metastases-directed local ablative radiotherapy (aRT) has been shown to be [...] Read more.
Progression of prostate-specific antigen (PSA) values after curative treatment of prostate cancer patients is common. Prostate-specific membrane antigen (PSMA-) PET imaging can identify patients with metachronous oligometastatic disease even at low PSA levels. Metastases-directed local ablative radiotherapy (aRT) has been shown to be a safe treatment option. In this prospective clinical trial, we evaluated local control and the pattern of tumor progression. Between 2014 and 2018, 63 patients received aRT of 89 metastases (MET) (68 lymph node (LN-)MET and 21 bony (OSS-)MET) with one of two radiation treatment schedules: 50 Gy in 2 Gy fractions in 34 MET or 30 Gy in 10 Gy fractions in 55 MET. The mean gross tumor volume and planning target volume were 2.2 and 14.9 mL, respectively. The median follow-up time was 40.7 months. Local progression occurred in seven MET, resulting in a local control rate of 93.5% after three years. Neither treatment schedule, target volume, nor type of lesion was associated with local progression. Regional progression in the proximity to the LN-MET was observed in 19 of 47 patients with at least one LN-MET (actuarial 59.3% free of regional progression after 3 years). In 33 patients (52%), a distant progression was reported. The median time to first tumor-related clinical event was 16.6 months, and 22.2% of patients had no tumor-related clinical event after three years. A total of 14 patients (22%) had another aRT. In conclusion, local ablative radiotherapy in patients with PSMA-PET staged oligometastatic prostate cancer may achieve local control, but regional or distant progression is common. Further studies are warranted, e.g., to define the optimal target volume coverage in LN-MET and OSS-MET. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
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13 pages, 3468 KiB  
Article
Primary Tumor Resection Decelerates Disease Progression in an Orthotopic Mouse Model of Metastatic Prostate Cancer
by Johannes Linxweiler, Turkan Hajili, Philip Zeuschner, Michael D. Menger, Michael Stöckle, Kerstin Junker and Matthias Saar
Cancers 2022, 14(3), 737; https://doi.org/10.3390/cancers14030737 - 31 Jan 2022
Cited by 13 | Viewed by 2935
Abstract
Radical prostatectomy in oligometastatic prostate cancer is a matter of intense debate. Besides avoiding local complications, it is hypothesized that primary tumor resection may result in better oncological outcomes. The aim of our study was to analyze the effect of primary tumor resection [...] Read more.
Radical prostatectomy in oligometastatic prostate cancer is a matter of intense debate. Besides avoiding local complications, it is hypothesized that primary tumor resection may result in better oncological outcomes. The aim of our study was to analyze the effect of primary tumor resection on disease progression in an orthotopic prostate cancer mouse model. First, the optimal time point for primary tumor resection, when metastases have already occurred, but the primary tumor is still resectable, was determined as 8 weeks after inoculation of 5 × 105 LuCaP136 cells. In a second in vivo experiment, 64 mice with metastatic prostate cancer were randomized into two groups, primary tumor resection or sham operation, and disease progression was followed up for 10 weeks. The technique of orthotopic primary tumor resection was successfully established. Compared with the sham operation group, mice with primary tumor resection showed a significantly longer survival (p < 0.001), a significantly slower PSA increase (p < 0.01), and a lower number of lung metastases (p = 0.073). In conclusion, primary tumor resection resulted in slower disease progression and longer survival in an orthotopic mouse model of metastatic prostate cancer. In future studies, this model will be used to unravel the molecular mechanisms of primary tumor/metastasis interaction in prostate cancer. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
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23 pages, 8643 KiB  
Article
Insulin-like Growth Factor-1 Influences Prostate Cancer Cell Growth and Invasion through an Integrin α3, α5, αV, and β1 Dependent Mechanism
by Carolin Siech, Jochen Rutz, Sebastian Maxeiner, Timothy Grein, Marlon Sonnenburg, Igor Tsaur, Felix K.-H. Chun and Roman A. Blaheta
Cancers 2022, 14(2), 363; https://doi.org/10.3390/cancers14020363 - 12 Jan 2022
Cited by 17 | Viewed by 2622
Abstract
Insulin-like growth factor-1 (IGF-1)-related signaling is associated with prostate cancer progression. Links were explored between IGF-1 and expression of integrin adhesion receptors to evaluate relevance for growth and migration. Androgen-resistant PC3 and DU145 and androgen-sensitive LNCaP and VCaP prostate cancer cells were stimulated [...] Read more.
Insulin-like growth factor-1 (IGF-1)-related signaling is associated with prostate cancer progression. Links were explored between IGF-1 and expression of integrin adhesion receptors to evaluate relevance for growth and migration. Androgen-resistant PC3 and DU145 and androgen-sensitive LNCaP and VCaP prostate cancer cells were stimulated with IGF-1 and tumor growth (all cell lines), adhesion and chemotaxis (PC3, DU145) were determined. Evaluation of Akt/mTOR-related proteins, focal adhesion kinase (FAK) and integrin α and β subtype expression followed. Akt knock-down was used to investigate its influence on integrin expression, while FAK blockade served to evaluate its influence on mTOR signaling. Integrin knock-down served to investigate its influence on tumor growth and chemotaxis. Stimulation with IGF-1 activated growth in PC3, DU145, and VCaP cells, and altered adhesion and chemotactic properties of DU145 and PC3 cells. This was associated with time-dependent alterations of the integrins α3, α5, αV, and β1, FAK phosphorylation and Akt/mTOR signaling. Integrin blockade or integrin knock-down in DU145 and PC3 cells altered tumor growth, adhesion, and chemotaxis. Akt knock-down (DU145 cells) cancelled the effect of IGF-1 on α3, α5, and αV integrins, whereas FAK blockade cancelled the effect of IGF-1 on mTOR signaling (DU145 cells). Prostate cancer growth and invasion are thus controlled by a fine-tuned network between IGF-1 driven integrin-FAK signaling and the Akt-mTOR pathway. Concerted targeting of integrin subtypes along with Akt-mTOR signaling could, therefore, open options to prevent progressive dissemination of prostate cancer. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
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12 pages, 1056 KiB  
Article
Health-Related Quality of Life following Cytoreductive Radical Prostatectomy in Patients with De-Novo Oligometastatic Prostate Cancer
by Michael Chaloupka, Lina Stoermer, Maria Apfelbeck, Alexander Buchner, Vera Wenter, Christian G. Stief, Thilo Westhofen and Alexander Kretschmer
Cancers 2021, 13(22), 5636; https://doi.org/10.3390/cancers13225636 - 11 Nov 2021
Cited by 11 | Viewed by 1713
Abstract
(1) Background: local treatment of the primary tumor has become a valid therapeutic option in de-novo oligo-metastatic prostate cancer (PC). However, evidence regarding radical prostatectomy (RP) in this setting is still subpar, and the effect of cytoreductive RP on postoperative health-related quality of [...] Read more.
(1) Background: local treatment of the primary tumor has become a valid therapeutic option in de-novo oligo-metastatic prostate cancer (PC). However, evidence regarding radical prostatectomy (RP) in this setting is still subpar, and the effect of cytoreductive RP on postoperative health-related quality of life (HRQOL) is still unclear. (2) Methods: for the current study, patients with de-novo oligo-metastatic PC (cM1-oligo), defined as ≤5 bone lesions in the preoperative staging, were included, and matched cohorts using the variables age, body-mass index (BMI), and pT-stage were generated. Patient-reported outcome measures (PROMS) were assessed pre- and postoperatively using the validated EORTC-QLQ-C30, IIEF-5, and ICIQ-SF questionnaires. The primary endpoint for univariate and multivariable analysis was good general HRQOL defined by previously validated cut-off values. (3) Results: in total, 1268 patients (n = 84 (7%) cM1-oligo) underwent RP between 2012 and 2020 at one tertiary care center. A matched cohort of 411 patients (n = 79 with oligo-metastatic bone disease (cM1-oligo) and n = 332 patients without clinical indication of metastatic disease (cM0)) was created. The median follow-up was 25mo. There was no significant difference in good general HRQOL rates between cM1-oligo-patients and cM0-patients before RP (45.6% vs. 55.2%, p = 0.186), and at time of follow-up (44% vs. 56%, p = 0.811). Global health status (GHS) worsened significantly in cM0-patients compared to baseline (−5, p = 0.001), whereas GHS did not change significantly in cM1-oligo-patients (+3.2, p = 0.381). In multivariate analysis stratified for good erectile function (IIEF5 > 18; OR 5.722, 95% CI 1.89–17.36, p = 0.002) and continence recovery (OR 1.671, 95% CI 1.03–2.70, p = 0.036), cM1-oligo was not an independent predictive feature for general HRQOL (OR 0.821, 95% CI 0.44–1.53, p = 0.536). (4) Conclusions: in this large contemporary retrospective analysis, we observed no significant difference in HRQOL in patients with the oligometastatic bone disease after cytoreductive radical prostatectomy, when compared to patients with localized disease at time of surgery. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
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Review

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10 pages, 269 KiB  
Review
Systemic Triple Therapy in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Ready for Prime Time or Still to Be Explored?
by Christian Thomas, Martin Baunacke, Holger H. H. Erb, Susanne Füssel, Kati Erdmann, Juliane Putz and Angelika Borkowetz
Cancers 2022, 14(1), 8; https://doi.org/10.3390/cancers14010008 - 21 Dec 2021
Cited by 14 | Viewed by 4288
Abstract
For decades, mono androgen deprivation therapy (ADT) has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last seven years demonstrating a significant survival advantage by combination treatment with standard ADT plus docetaxel or [...] Read more.
For decades, mono androgen deprivation therapy (ADT) has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last seven years demonstrating a significant survival advantage by combination treatment with standard ADT plus docetaxel or androgen receptor-axis-targeted therapy (ARAT) compared to ADT monotherapy. As a result, overall survival can be prolonged by at least 18 months. Recently published congress data of the PEACE-1 study suggests that in the future, triple therapy might be the new gold standard. In addition to this study, which has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel, several other phase III triple therapy studies are currently ongoing. The different modes of action that are investigated reach from AR-targeting over mitotic inhibition and immunotherapy to PARP and AKT inhibition. In this review we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
20 pages, 5513 KiB  
Review
Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer
by Celina Ebersbach, Alicia-Marie K. Beier, Christian Thomas and Holger H. H. Erb
Cancers 2021, 13(19), 4854; https://doi.org/10.3390/cancers13194854 - 28 Sep 2021
Cited by 16 | Viewed by 3371
Abstract
Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate [...] Read more.
Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials. Full article
(This article belongs to the Special Issue New Advances in Metastatic Prostate Cancer)
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