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Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and...
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Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 8653

Special Issue Editor

Dr. Alan P. Lombard

E-Mail Website
Guest Editor
1. Department of Urologic Surgery, University of California Davis, Sacramento, CA 95817, USA
2. Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95616, USA
Interests: prostate cancer; AR pathway inhibition; PARP inhibitors; therapeutic response and resistance; drug-tolerant persister cancer cells

Special Issue Information

Dear Colleagues,

The clinical landscape for advanced prostate cancer is rapidly changing. The field is quickly moving toward a targeted paradigm, where individualized patient tumor characteristics will guide treatment decisions, leading to tailored, improved outcomes. Current progress toward the promise of precision medicine for prostate cancer includes PARP inhibitor use for the treatment of tumors with DNA repair defects, pembrolizumab (PD-1 inhibitor) for MMR defective tumors, and the recent approval of 177Lu-PSMA-617 (Pluvicto) for PSMA-positive mCRPC. Rational combinations of new and available therapies are also improving patient management. Notably, our evolving understanding of AR pathway inhibitors and PARP inhibition has led to the approval of combinations of these agents. As our understanding of prostate cancer molecular characteristics, use of biomarkers for patient stratification, and drug synergies improves, new approaches are expected to continue to revolutionize how we treat this disease. In this Special Issue, we seek to highlight cutting-edge research advances working to promote and incorporate the use of targeted and rational approaches for advanced and intractable prostate cancer. Studies detailing basic, translational, and clinical work to advance targeted and rational combination strategies are highly encouraged. Work to develop, understand, and incorporate clinical biomarkers to better stratify patients for treatment are also welcomed. Additionally, reviews summarizing different aspects of targeted therapy for prostate cancer and current clinical findings and perspectives will be warmly accepted for review. We express our warmest thanks for considering this opportunity to highlight the latest research in treating advanced prostate cancer.

Dr. Alan P. Lombard
Guest Editor

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Keywords

  • prostate cancer
  • precision medicine
  • targeted therapeutics
  • rational drug combinations
  • clinical biomarkers

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Published Papers (5 papers)

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Research

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19 pages, 11457 KB  
Article
Characterizing Response to PARP Inhibitor Treatment Combinations in Advanced Prostate Cancer
by Bryan Correa Gonzalez, Akshaya Karthikeyan, Love A. Moore, Anamitra Bhaumik, Ethan Sandoval, Marion Hardy, John D. McPherson, Hong Li, Mamta Parikh, Marc Dall’Era, Allen C. Gao and Alan P. Lombard
Biomedicines 2026, 14(5), 949; https://doi.org/10.3390/biomedicines14050949 - 22 Apr 2026
Viewed by 520
Abstract
Background/Objectives: Combinations of PARP inhibitors (PARPi) and androgen receptor pathway inhibitors (ARPi) have led to clinical success in treating advanced prostate cancer. However, it is unclear where in the clinical paradigm these combinations will fare best, and their mechanism of action remains [...] Read more.
Background/Objectives: Combinations of PARP inhibitors (PARPi) and androgen receptor pathway inhibitors (ARPi) have led to clinical success in treating advanced prostate cancer. However, it is unclear where in the clinical paradigm these combinations will fare best, and their mechanism of action remains unclear. We sought to address open questions and explore alternative strategies to enhance PARPi efficacy. Methods: Viability and morphology were assessed in response to (1) abiraterone, olaparib, or combination and (2) enzalutamide, talazoparib, or combination in castration-resistant C4-2B cells and abiraterone- or enzalutamide-resistant derivative cell models (ARPi-resistant). The efficacy of the ATM inhibitor lartesertib with and without a PARPi was also determined. Western blots and RNA-sequencing were used to interrogate the mechanistic effects of treatment. Results: PARPi and ARPi combinations were effective in all models but provided the most benefit in ARPi-sensitive C4-2B cells. Mechanistically, ARPi was not found to affect homologous recombination repair gene expression but may increase PARP activity. Prolonged PARP inhibition was found to increase the expression of AR target genes, and PARPi pre-treatment increased sensitivity to enzalutamide. ATM inhibition significantly increases PARPi efficacy and appears to outperform ARPi-containing combinations in ARPi-resistant models. Conclusions: PARPi and ARPi combinations are effective in ARPi-resistant models, but efficacy appears stronger in ARPi-sensitive CRPC cells. Presented findings support a novel hypothesis that PARP inhibition may increase ARPi sensitivity with increasing AR activity. Additionally, ATM inhibition may provide more benefit than an ARPi in combination with a PARPi in ARPi-resistant settings. These findings support continued PARPi development for improving patient outcomes. Full article
(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)
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14 pages, 1518 KB  
Article
Differentially Expressed miRNA of Prostate Cancer Compared with Benign Prostatic Hyperplasia Tissues: VAMP Associated Protein B Could Be Used for New Targets and Biomarkers of Prostate Cancer
by Jae Heon Kim, Ahrim Moon, Miho Song, Kwang Woo Lee, Su Min Seo, Hui Ji Kim, Luis Alfonso Pefianco, Kevin Andrean, Seongho Ryu and Yun-Seob Song
Biomedicines 2025, 13(12), 2922; https://doi.org/10.3390/biomedicines13122922 - 28 Nov 2025
Cited by 1 | Viewed by 940
Abstract
Background/Objectives: This NGS-based study sought to identify novel molecular markers for prostate cancer by comparing miRNA expression in cancer and benign prostatic hyperplasia (BPH) tissues. Methods: Using high-throughput sequencing and stringent statistical criteria, the study identified eleven significantly dysregulated miRNAs (five [...] Read more.
Background/Objectives: This NGS-based study sought to identify novel molecular markers for prostate cancer by comparing miRNA expression in cancer and benign prostatic hyperplasia (BPH) tissues. Methods: Using high-throughput sequencing and stringent statistical criteria, the study identified eleven significantly dysregulated miRNAs (five downregulated, six upregulated) that differentiate the two conditions. Enrichment analyses linked these miRNAs to several key cancer-associated pathways, including PI3K–Akt and ErbB signaling. Results: Crucially, the protein vesicle-associated membrane protein-associated protein B (VAPB) was pinpointed as a central hub, regulated by three downregulated miRNAs (miR-143-3p, miR-221-3p, and miR-222-3p). Since VAPB has not been widely studied in prostate cancer, it represents a promising, novel candidate for both diagnosis and therapeutic targeting. Conclusions: Our NGS-based analysis revealed a distinct miRNA expression signature that differentiates prostate cancer from BPH. The downregulation of several tumor-suppressive miRNAs (with concomitant upregulation of oncogenic miRNAs) in prostate cancer may contribute to malignancy—including the de-repression of novel targets like VAPB, which we identify as a promising new biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)
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19 pages, 3069 KB  
Article
Cyclophilin Inhibitor Rencofilstat Combined with Proteasome Inhibitor Ixazomib Increases Proteotoxic Cell Death in Advanced Prostate Cancer Cells with Minimal Effects on Non-Cancer Cells
by Carlos Perez-Stable, Alicia de las Pozas, Medhi Wangpaichitr, Robert T. Foster and Daren R. Ure
Biomedicines 2025, 13(10), 2442; https://doi.org/10.3390/biomedicines13102442 - 7 Oct 2025
Viewed by 1516
Abstract
Background/Objective: Proteotoxic stress induced by inhibitors of the ubiquitin–proteasome system has been successful in multiple myeloma but not in solid cancers such as prostate cancer. Our objective is to find a combination with proteasome inhibitors that increases apoptotic cell death in all types [...] Read more.
Background/Objective: Proteotoxic stress induced by inhibitors of the ubiquitin–proteasome system has been successful in multiple myeloma but not in solid cancers such as prostate cancer. Our objective is to find a combination with proteasome inhibitors that increases apoptotic cell death in all types of prostate cancer without harming non-cancer cells. Methods: The effectiveness of rencofilstat, a pan-cyclophilin inhibitor, combined with the ixazomib proteasome inhibitor, was investigated in multiple prostate cancer and non-cancer cells. Inducible knockdown of stress response XBP1s and cyclophilins A/B and inducible expression of XBP1s and cyclophilin B were developed in prostate cancer to determine functional roles. Results: Rencofilstat + ixazomib increased apoptotic cell death in prostate cancer but not in non-cancer cells. We investigated the effects on XBP1s and PERK, important unfolded protein response factors required for cells to survive proteotoxic stress. The results revealed that XBP1s had a pro-survival role early, but maintenance at later times of rencofilstat + ixazomib treatment resulted in cell death. In addition, decreased PERK and phospho-eIF2α likely maintained protein synthesis to further enhance proteotoxic stress. In contrast, rencofilstat + ixazomib did not alter XBP1s or PERK in non-cancer cells. Additional genetic experiments showed that the RCF targets cyclophilins A, B, and D had protective effects. Rencofilstat increased extracellular secretion of cyclophilin B, but rencofilstat + ixazomib reduced glycosylation and, likely, the biological function of CD147 (CypB receptor) and decreased downstream ERK signaling. Conclusions: Rencofilstat + ixazomib may be a new strategy for increasing proteotoxic stress and apoptotic cell death in advanced prostate cancer cells with less toxic side effects. Full article
(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)
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15 pages, 1195 KB  
Article
Long-Term Outcomes After High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy in Very High-Risk Prostate Cancer: A 24-Year Follow-Up
by Pedro J. Prada Gómez, Ana L. Rivero Pérez, Joaquín Carballido Rodríguez, Javier Anchuelo Latorre, Rosa Fabregat Borrás, Marina Gutiérrez Ruiz, Cristina Rodríguez-Acosta Caballero, Carlos F. Carrascal Gordillo, Maria P. Galdós Barroso and Paola A. Navarrete Solano
Biomedicines 2025, 13(6), 1310; https://doi.org/10.3390/biomedicines13061310 - 27 May 2025
Cited by 3 | Viewed by 3709
Abstract
Purpose: To evaluate the long-term oncological outcomes and toxicity profile based on 24 years of follow-up in patients with localized very high-risk prostate cancer (VHR PCa) treated with a combination of high-dose-rate brachytherapy (HDR-BT) and pelvic external beam radiation therapy (EBRT). Methods [...] Read more.
Purpose: To evaluate the long-term oncological outcomes and toxicity profile based on 24 years of follow-up in patients with localized very high-risk prostate cancer (VHR PCa) treated with a combination of high-dose-rate brachytherapy (HDR-BT) and pelvic external beam radiation therapy (EBRT). Methods: A retrospective analysis was conducted on 87 patients with VHR PCa, classified according to National Comprehensive Cancer Network (NCCN) criteria, who received HDR-BT and EBRT. Androgen deprivation therapy (ADT) was administered to 72 patients (82.8%). The primary endpoints were biochemical control and cancer-specific survival (CSS), while the secondary endpoints included local control rates, tumor-free survival (TFS), overall survival (OS), and treatment-related toxicity. Results: The 24-year biochemical control rate was 68% (standard deviation [SD]: ±4%), while CSS and TFS at 24 years were 82% (SD ±4%) and 78% (SD ±4%), respectively. Local control rates remained at 98% at 24 years. Furthermore, the OS rate at 24 years was 30%. Multivariate Cox regression analysis identified the T category in the TNM classification as the only factor significantly associated with biochemical control, with 24-year rates of 69%, 71%, and 50% for patients with T-classifications of ≤T2c, T3a, and T3b-T4, respectively (p = 0.024). Notably, no grade ≥3 late toxicities were observed during the follow-up period. Conclusions: The 24-year outcomes support the viability and therapeutic efficacy of EBRT combined with a conformal HDR-BT boost for patients with VHR PCa. Full article
(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)
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Review

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29 pages, 847 KB  
Review
Focusing on Prostate-Specific Membrane Antigen in Precision Diagnosis and Treatment of Prostate Cancer
by Xinyi Ren, Lingling Zhang, Ran An, Hongchen Song, Mingjun Shi and Zhenchang Wang
Biomedicines 2026, 14(2), 482; https://doi.org/10.3390/biomedicines14020482 - 22 Feb 2026
Viewed by 1100
Abstract
Prostate cancer (PCa) is the most common malignant tumor of the male genitourinary system, and its incidence and mortality have shown a marked global increase in recent years. Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein highly expressed in PCa cells, has [...] Read more.
Prostate cancer (PCa) is the most common malignant tumor of the male genitourinary system, and its incidence and mortality have shown a marked global increase in recent years. Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein highly expressed in PCa cells, has emerged as a vital molecular target in the field of PCa precision diagnosis and therapy. In recent years, significant advances have been achieved in PSMA-based molecular imaging, radioligand therapy, and the development of novel targeted drugs. This review aims to summarize and critically discuss recent advances in PSMA-targeted molecular imaging, radioligand therapy, and emerging therapeutic strategies, highlighting their roles in precision diagnosis and personalized treatment of PCa. PSMA positron emission tomography/computed tomography (PET/CT) imaging using radionuclides such as 68Ga and 18F has markedly improved the accuracy of primary tumor staging, localization of recurrent lesions, and therapeutic response assessment. Radioligand therapies, such as 177Lu-PSMA-617 and 225Ac-PSMA-617, have prolonged survival and demonstrated symptomatic benefits in multiple clinical trials, and are now applied in early disease stages, including chemotherapy-naïve and hormone-sensitive settings. Meanwhile, PSMA-targeted antibodies and antibody–drug conjugates (PSMA-ADCs), as well as bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, are constantly being optimized and show promising clinical potential. Furthermore, PSMA-targeted nanoplatforms enable precise delivery of chemotherapeutic agents, photosensitizers, or imaging probes, achieving integrated diagnosis and therapy with multimodal imaging guidance, and offering new strategies for individualized treatment. Taken together, the evidence summarized in this review highlights PSMA as a pivotal molecular target supporting precision diagnosis and personalized treatment across the continuum of prostate cancer management. Full article
(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)
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