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Cancers
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Castration-Resistant Prostate Cancer: Progress and Promise
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Castration-Resistant Prostate Cancer: Progress and Promise

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

Deadline for manuscript submissions: closed (5 December 2024) | Viewed by 6801

Special Issue Editors

Dr. Shiv Verma

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Guest Editor
Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Interests: translational research; castrate-resistant prostate cancer; stem cell and CRPC; cancer cell metabolism; data science; cell signaling; immunotherapy
Special Issues, Collections and Topics in MDPI journals
Dr. Vaibhav Singh

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Guest Editor
Cleveland Clinic Foundation, Cleveland, OH, USA
Interests: proteomics; translational research; antibody and therapeutic; brain research; neurodegenerative disease; cell signaling; artificial intelligence; immunology
Special Issues, Collections and Topics in MDPI journals
Dr. Man Mohan

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Guest Editor
Senior Scientist, Hematology Department, St Jude Children's Research Hospital, Memphis, TN, USA
Interests: cancer; therapeutic development; translational research; cell signaling; immunology

Special Issue Information

Dear Colleagues,

The advanced form of prostate cancer is designated metastatic castration-resistant prostate cancer (mCRPC), which spreads beyond the prostate gland and for which hormone therapy is no longer effective in slowing down disease progression. mCRPC occurs when prostate cancer evolves to resist standard treatment with androgen deprivation therapy (ADT), which blocks the production and signaling activity of hormones called androgens (such as testosterone) that ensure the cancer’s growth. An estimated 50% of diagnosed cases progress to mCRPC within 3 years of diagnosis and this aggressive form of the disease remains lethal despite therapeutic advances. Patients diagnosed with mCRPC have survival ranges from 3 to 78 months. mCRPC remains a clinically challenging late-stage cancer with no curative treatment options. The current treatment options available for mCRPC are the hormonal drugs enzalutamide (brand name XTANDI) and abiraterone (ZYTIGA, which is given with prednisone), which are often used as the first line of therapy for CRPC/mCRPC patients. Moreover, Docetaxel (chemotherapy) is used in patients who are non-responsive to enzalutamide or abiraterone. Recently, the clinical guidelines made some changes in the treatment of CRPC patients; now, mutational testing and the analysis of marker genes such as BRCA2, BRCA1, CHECK2, ATM, and a few others are clinically adaptive to predict the effectiveness of new treatments, including the immune system, In recent years, what has changed in the treatment of mCRPC is that clinical guidelines now include mutational testing and analysis of markers to predict the potential effectiveness of newer treatments that involve immunotherapy.

Dr. Shiv Verma
Dr. Vaibhav Singh
Dr. Man Mohan
Guest Editors

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Keywords

  • castrate-resistant prostate cancer (CRPC)
  • prostate cancer
  • treatment
  • a new therapy
  • drug-resistant
  • marker genes
  • bone metastasis
  • androgen receptor (AR)
  • enzalutamid
  • e abiraterone acetate
  • Docetaxel

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Published Papers (4 papers)

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Research

14 pages, 5557 KiB  
Article
Is Extraordinary Response and Long-Term Remission of Metastatic Castration-Resistant Prostate Cancer (mCRPC) After [¹⁷⁷Lu]Lu-PSMA Radioligand Therapy Due to an Immunomodulatory Effect (Radiovaccination)? A Dual Center Experience on Super-Responders
by Masha Maharaj, Elisabetta Perrone, Ralph M. Wirtz, Lucille Heslop, Trisha Govender, Nisaar A. Korowlay, Kriti Ghai, Tanay Parkar and Richard P. Baum
Cancers 2025, 17(3), 476; https://doi.org/10.3390/cancers17030476 - 31 Jan 2025
Viewed by 1575
Abstract
Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([177Lu]Lu-PSMA) is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The aim of our study was to evaluate clinical variables of patients with extreme response to PRLT and [...] Read more.
Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([177Lu]Lu-PSMA) is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The aim of our study was to evaluate clinical variables of patients with extreme response to PRLT and to assess its immunomodulatory potential. Methods: This retrospective study included 36 patients from two centers achieving extreme response after [¹⁷⁷Lu]Lu-PSMA PRLT. The primary outcomes were the duration of maintained response in months (MR) and improvement post-therapy—clinically, serologically, and on molecular (PET/CT) imaging. We examined several variables, including pathology, gene sequencing, baseline PSA, Gleason score, prior therapies, number of PRLT cycles, and pattern of disease, to identify potential factors that may influence the extreme response. Results: Between 2018 and mid-September 2024, 36 men with mCRPC received a mean of three cycles of [177Lu]Lu-PSMA PRLT. Patients were subgrouped according to clinical variables versus MR. A total of 17 patients had ≥12 months MR (17/36, 47%). The longest duration of MR was 99 months and a mean of 17.44 months (95% CI 10.05–24.84). Previous lines of treatment were evaluated for MR, p = 0.172. Pattern of disease (bone, lymph node, liver, and peritoneal) was evaluated for MR, p = 0.721. The Gleason score was evaluated for MR, p = 0.871. Patients with known BRCA sequencing status (n = 12) were analyzed with mean MR: BRCA1/2 wild-type, 6/12 (50%), 6.67 months; BRCA 1/2 negative, 1/12 (8.33%), 7 months; BRCA germline negative and somatic positive, 1/12 (8.33%), 36 months; BRCA germline negative, somatic negative, 2/12 (16.67%), 27 months; and BRCA 2 positive, 2/12 (16.67%), 43 months. Conclusions: We propose there may be intrinsic mechanisms suggesting the immunomodulatory enhancement of ionizing radiation, primarily driving extreme responses. Full article
(This article belongs to the Special Issue Castration-Resistant Prostate Cancer: Progress and Promise)
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17 pages, 4131 KiB  
Article
Long-Term Safety and Survival Outcomes of [225Ac]Ac-PSMA (Prostate-Specific Membrane Antigen) and [225Ac]Ac-/[177Lu]Lu-PSMA (TANDEM) Radioligand Therapy (PRLT) in Metastatic Castration-Resistant Prostate Cancer
by Elisabetta Perrone, Alessandro Giordano, Maria Lucia Calcagni, Lucia Leccisotti, Roberto Moretti, Aleksandr Eismant, Kriti Ghai, Tanay Parkar, Aditi Mishra, Axel Heidenreich, Ralph M. Wirtz, Jörg Müller, Lukas Greifenstein and Richard P. Baum
Cancers 2025, 17(3), 405; https://doi.org/10.3390/cancers17030405 - 26 Jan 2025
Viewed by 1864
Abstract
This study aims to retrospectively assess the safety of [225Ac]Ac-PSMA-PRLT, both as monotherapy and in combination (TANDEM) with Lutetium-177, concerning tolerance after the radiopharmaceutical administration and long-term safety, its impact on salivary glands’ function, overall survival (OS), and follow-up duration. Between [...] Read more.
This study aims to retrospectively assess the safety of [225Ac]Ac-PSMA-PRLT, both as monotherapy and in combination (TANDEM) with Lutetium-177, concerning tolerance after the radiopharmaceutical administration and long-term safety, its impact on salivary glands’ function, overall survival (OS), and follow-up duration. Between December 2020 and September 2024, 89 patients received a total of 151 cycles of [225Ac]Ac-PSMA-PRLT. Patients with at least one follow-up (n = 71) were included in the analysis to evaluate xerostomia, as well as long-term hematological, renal, and hepatic toxicities, graded according to CTCAE v5.0. The most common adverse event after the radiopharmaceutical administration was flare pain (n = 16). As of the time of analysis, 68 patients had passed away (76.4%; range of survival 5 days to 39 months, median 7 months), while 21 patients were still alive (23.6%; follow-up duration: 1–33 months). Severe (G3/G4) long-term adverse events were rare, with 15 cases of G3 anemia (21.1%), 6 cases of G3 leukocytopenia (8.4%), and 14 cases of G3/G4 thrombocytopenia (19.7%). Hematological toxicity was primarily associated with severe bone marrow involvement or prior chemotherapy. Additionally, one case of G3 nephrotoxicity (1.4%) and six cases of G3 hepatotoxicity (8.4%) were observed. Only nine patients (12.7%) reported de novo xerostomia (G1/G2). In conclusion, this study demonstrates that [225Ac]Ac-PSMA PRLT, both as monotherapy and combined with [177Lu]Lu-PSMA as TANDEM PRLT, is generally safe in terms of both tolerance after the radiopharmaceutical administration and long-term toxicity. Full article
(This article belongs to the Special Issue Castration-Resistant Prostate Cancer: Progress and Promise)
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16 pages, 2458 KiB  
Article
DNA Repair Capacity and Clinicopathological Characteristics in Puerto Rican Hispanic/Latino Patients with Metastatic Castration-Resistant Prostate Cancer
by Jaime Matta, Carmen Ortiz-Sánchez, Jarline Encarnación-Medina, Stephanie Torres-Caraballo, Jose Oliveras, Jong Park, Monica M. Arroyo and Gilberto Ruiz-Deya
Cancers 2025, 17(2), 279; https://doi.org/10.3390/cancers17020279 - 16 Jan 2025
Viewed by 771
Abstract
Background: Prostate cancer (PCa) accounts for 22% of the new cases diagnosed in Hispanic/Latino (H/L) men in the US. PCa has the highest incidence (38.3%) and mortality (16.4%) among all types of cancer diagnosed in Puerto Rico. We previously showed that PCa patients [...] Read more.
Background: Prostate cancer (PCa) accounts for 22% of the new cases diagnosed in Hispanic/Latino (H/L) men in the US. PCa has the highest incidence (38.3%) and mortality (16.4%) among all types of cancer diagnosed in Puerto Rico. We previously showed that PCa patients (n = 41) have a significant reduction of 59% in their levels of DNA repair capacity (DRC) when compared to controls (n = 14). This study aimed to evaluate DRC levels through the nucleotide excision repair (NER) pathway for the first time in 16 Puerto Rican H/L men with metastatic castration-resistant PCa (mCRPCa) while establishing comparisons with controls and PCa patients with indolent and aggressive disease. Methods: Blood samples and clinicopathological data from PCa cases (n = 71) and controls (n = 25) were evaluated. PCa cases were stratified into mCRPCa (n = 16), aggressive (n = 31), and indolent (n = 24). DRC levels through NER were measured in lymphocytes with the CometChip assay. The stratification by Gleason score (GS) was GS6 (n = 7), GS7 (n = 23), GS ≥ 8 (n = 20), and mCRPCa patients (n = 16). Results: Significant statistical differences were found when comparing the DRC values of the controls with any other of the four PCa patient groups. mCRPCa patients had the lowest mean DRC level of all four patient groups studied. The mean DRC level of mCRPCa patients was 6.65%, and compared to the controls, this represented a statistically significant reduction of 62% (p < 0.0001). Further analysis was performed to evaluate the contributions of age, anthropometric measurements, and prostate-specific antigen (PSA) levels to the DRC. Kaplan–Meier curves of mCRPCa revealed that survival probability decreased by approximately 50% by 30 months. This pilot study uses a blood-based phenotypic assay to present the first report of mCRPCa in Puerto Rican men and at a global level of DRC levels of mCRPCa patients. Conclusions: This study evaluated DRC levels through the NER pathway for the first time in 16 Puerto Rican H/L men with mCRPCa. Significant differences in DRC values were found between the controls and the three PCa patient groups. Kaplan–Meier curves revealed that survival probability decreased by approximately 50% by 30 months, and only 20% of the cohort was alive at 50 months, confirming the lethality of mCRPCa in this H/L population. This pilot study represents the first report of metastatic PCa in Puerto Rican men at a global level of DRC levels of mCRPCa patients using a blood-based phenotypic assay. Full article
(This article belongs to the Special Issue Castration-Resistant Prostate Cancer: Progress and Promise)
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13 pages, 706 KiB  
Article
Prediction of PSA Response after Dexamethasone Switch during Abiraterone Acetate + Prednisolone Treatment of Metastatic Castration-Resistant Prostate Cancer Patients
by Bertalan Fekete, Krisztina Biró, Fruzsina Gyergyay, Nándor Polk, Orsolya Horváth, Lajos Géczi, Attila Patócs and Barna Budai
Cancers 2024, 16(15), 2760; https://doi.org/10.3390/cancers16152760 - 3 Aug 2024
Viewed by 1537
Abstract
Background: The aim was to elaborate a predictive model to find responders for the corticosteroid switch (from prednisolone to dexamethasone) at the first prostate-specific antigen (PSA) progression (≥25% increase) during abiraterone acetate (AA) treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: If [...] Read more.
Background: The aim was to elaborate a predictive model to find responders for the corticosteroid switch (from prednisolone to dexamethasone) at the first prostate-specific antigen (PSA) progression (≥25% increase) during abiraterone acetate (AA) treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: If PSA has decreased (≥25%) after switch, patients were considered responders. Logistic regression of 19 dichotomized parameters from routine laboratory and patients’ history was used to find the best model in a cohort of 67 patients. The model was validated in another cohort of 42 patients. Results: The model provided 92.5% and 90.5% accuracy in the testing and the validation cohorts, respectively. Overall the accuracy was 91.7%. The AUC of ROC curve was 0.92 (95% CI 0.85–0.96). After a median follow-up of 27.9 (26.3–84) months, the median AA+dexamethasone treatment duration (TD) in non-responders and responders was 4.7 (3.1–6.5) and 11.1 (8.5–12.9) months and the median overall survival (OS) was 23.2 (15.6–25.8) and 33.5 (26.1–38) months, respectively. Multivariate Cox regression revealed that responsiveness was an independent marker of TD and OS. Conclusions: A high accuracy model was developed for mCRPC patients in predicting cases which might benefit from the switch. For non-responders, induction of the next systemic treatment is indicated. Full article
(This article belongs to the Special Issue Castration-Resistant Prostate Cancer: Progress and Promise)
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