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Prostate-Specific Membrane Antigen (PSMA)-Targeted Radionuclide Therapy in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: 15 August 2026 | Viewed by 452

Editors

Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Interests: radiochemistry; PET Imaging; cancer metabolism; infection detection; PSMA-based radiopharmaceuticals

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Guest Editor
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Interests: PET tracers; radiosynthesis; PET imaging; cancer; pharmacodynamics
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Special Issue Information

Dear Colleagues,

Prostate cancer (PCa) is the most commonly diagnosed malignancy in men worldwide and the second leading cause of cancer-related death in Western countries. The prostate-specific membrane antigen (PSMA) is highly specific to prostatic adenocarcinoma and is significantly elevated in PCa. The rapid constitutive internalization of PSMA-targeted radioligands makes PSMA an excellent target for imaging diagnostics and targeted radionuclide therapy (TRNT) for PCa and its metastases.

In recent years, PSMA-targeted radionuclide therapy (PSMA-TRNT) has emerged as a promising alternative to traditional treatments for metastatic castration-resistant prostate cancer (mCRPC). Recognizing its potential, the U.S. Food and Drug Administration (FDA) granted a Breakthrough Therapy designation to ¹⁷⁷Lu-PSMA-617 in 2022 for the treatment of mCRPC. Ongoing studies on primary PSMA-TRNT and combination therapies are expected to provide valuable insights into optimizing treatment strategies.

Despite these advancements, challenges and limitations remain in fully integrating PSMA-TRNT into routine clinical practice. This Special Issue aims to explore these challenges, assess the current state of the field, and discuss future directions for advancing PSMA-targeted radionuclide therapy.

We invite the submission of original research articles and reviews covering but not limited to the following topics:

  1. Biological mechanisms of PSMA expression, regulation, and function.
    The therapeutic efficacy of PSMA-TRNT depends on PSMA expression levels in tumors. However, the heterogeneity of PSMA expression and its downregulation in advanced mCRPC pose significant challenges. A deeper understanding of the biology of PSMA regulation could aid in developing novel strategies to enhance therapeutic response and safety.
  2. Development of novel PSMA-targeted radioligands.
    Structural modifications of radioligands—including alterations to radionuclides, chelators, linkers, and PSMA-targeting motifs—can influence stability, toxicity, biodistribution, pharmacokinetics, and off-target effects. Advancing radioligand design will expand personalized diagnostic and therapeutic options.
  3. Evaluation of PSMA-TRNT and combination therapy across different stages and subtypes of PCa.
    The variability in inter- and intra-patient PSMA expression in prostate cancer (PCa) necessitates optimal patient selection, resistance mechanism assessment, and co-targeting strategies to maximize the clinical benefits of PSMA-targeted radionuclide therapy (PSMA-TRNT). Additionally, synergistic combination therapies may help overcome therapeutic limitations and mitigate adverse effects, leading to more effective treatment approaches.
  4. Evaluation of PSMA-TRNT in other solid tumor models.
    Beyond prostate cancer, the PSMA is overexpressed in the neovasculature of various solid tumors, including glioma. This presents an opportunity to expand the application of PSMA-TRNT for the treatment of other solid tumors.

We welcome contributions that advance the understanding and clinical application of PSMA-targeted radionuclide therapy in prostate cancer treatment.

Dr. Ning Zhou
Dr. Sashi Debnath
Guest Editors

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Keywords

  • PSMA-TRNT
  • radioligand therapy
  • radionuclide therapy
  • theranostics
  • prostate-specific membrane antigen (PSMA)
  • PSMA targeted
  • PSMA ligands
  • prostate cancer (PCa)
  • metastatic castration-resistant prostate cancer (mCRPC)

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Published Papers (1 paper)

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Review

14 pages, 656 KB  
Review
PSMA-Targeted Radioligand Therapy Beyond the Post-Taxane Setting: A Review of Evidence Across the Prostate Cancer Spectrum
by Kaiying Wang, Daanesh Huned Hassanbhai, Roxanne Yong Ai Teo, Chloe Shu Hui Ong, Kah Wai Lai, Si Xuan Koo, Wai Loon Yam and Joshua Yi Min Tung
Cancers 2026, 18(13), 2161; https://doi.org/10.3390/cancers18132161 (registering DOI) - 5 Jul 2026
Abstract
Lutetium-177-PSMA-617 (Lu-PSMA) radioligand therapy (RLT) is established in metastatic castration-resistant prostate cancer (mCRPC), with regulatory approvals based on the VISION and TheraP trials. Subsequent trials have extended the evidence to taxane-naive mCRPC (PSMAfore) and demonstrated that combining Lu-PSMA with enzalutamide yields a significant [...] Read more.
Lutetium-177-PSMA-617 (Lu-PSMA) radioligand therapy (RLT) is established in metastatic castration-resistant prostate cancer (mCRPC), with regulatory approvals based on the VISION and TheraP trials. Subsequent trials have extended the evidence to taxane-naive mCRPC (PSMAfore) and demonstrated that combining Lu-PSMA with enzalutamide yields a significant overall survival benefit over enzalutamide alone (ENZA-p). However, higher and more homogeneous PSMA expression in treatment-naive disease, combined with lower tumor burden and preserved bone marrow reserve, provides a biological rationale for deploying RLT earlier in the disease course. In metastatic hormone-sensitive prostate cancer (mHSPC), the Phase III PSMAddition trial reported improved radiographic progression-free survival when Lu-PSMA was added to standard androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitor (ARPI), and the Phase II UpFrontPSMA trial demonstrated enhanced biochemical responses with Lu-PSMA induction before docetaxel. In oligometastatic and oligorecurrent disease, the BULLSEYE and LUNAR trials have shown progression-free survival benefits, raising the possibility of deferring androgen deprivation therapy and its associated morbidity. Meanwhile, next-generation radionuclides, including actinium-225 (WARMTH) and the dual beta-Auger emitter terbium-161 (VIOLET), are entering clinical development to address the radiobiological limitations of Lutetium-177. This review synthesizes the evidence for PSMA-targeted radioligand therapy across the prostate cancer disease continuum and discusses patient selection, treatment sequencing, and the access and cost-effectiveness considerations that will shape adoption in earlier disease settings. Full article
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