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

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

Manuscript Submission Information

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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.

• 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)