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Radionuclide Therapy in Prostate Cancer: From Standalone to Combination PSMA Theranostics
Shahneen Sandhu1,2, Christina Guo3,4, Michael S Hofman5,6
1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Abstract:
Despite significant advances in therapeutic developments for prostate cancer over the last 2 decades, metastatic prostate cancer remains a lethal disease. Prostate-specific membrane antigen (PSMA), which is markedly overexpressed in prostate cancer cells and metastatic sites but has low normal-tissue expression, has emerged as an important theranostic target for this disease. Both β-emitting and α-emitting PSMA-targeted radionuclide therapy (RNT) are in clinical development. Several of these agents have already shown promising activity; however, a subset of patients have primary resistant disease, and secondary resistance invariably occurs. Further, the effect of these therapies on healthy organs limits their therapeutic window. Elucidating the biology of PSMA and characterizing the pharmacokinetic and pharmacodynamic properties of PSMA-targeted RNT and mechanisms of resistance will facilitate therapeutic approaches aimed at improving efficacy and safety. In this review, we provide an overview of existing PSMA-targeting RNT and novel RNT combinatorial approaches, such as those with novel hormonal agents, poly-[adenosine diphosphate-ribose]-polymerase inhibitors and immunotherapy, currently under investigation.
Insights
Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy shows promise for metastatic prostate cancer. Research is ongoing to overcome resistance and improve safety for better treatment outcomes.
Area of Science:
- Oncology
- Nuclear Medicine
- Radiopharmaceutical Therapy
Background:
- Metastatic prostate cancer remains a significant cause of cancer-related deaths despite therapeutic advances.
- Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, making it a key target for theranostics.
- PSMA-targeted radionuclide therapy (RNT) using beta or alpha emitters is under clinical investigation.
Purpose of the Study:
- To review current PSMA-targeted RNT strategies for metastatic prostate cancer.
- To discuss challenges including primary and secondary resistance to RNT.
- To explore novel combinatorial approaches to enhance RNT efficacy and safety.
Main Methods:
- Literature review of existing PSMA-targeted RNT agents.
- Analysis of pharmacokinetic and pharmacodynamic properties of RNT.
- Examination of resistance mechanisms and strategies to overcome them.
- Overview of emerging combinatorial therapies.
Main Results:
- Several PSMA-targeted RNT agents demonstrate promising activity in clinical development.
- Primary resistance and acquired resistance are significant limitations.
- Off-target toxicity affects the therapeutic window of current RNT.
- Understanding PSMA biology is crucial for optimizing RNT.
Conclusions:
- PSMA-targeted RNT offers a viable therapeutic avenue for metastatic prostate cancer.
- Further research into resistance mechanisms and combination strategies is essential.
- Optimizing RNT requires a deeper understanding of PSMA biology and therapy dynamics to improve patient outcomes.
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