Glioblastoma Targeted Alpha Therapy

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

• Glioblastoma Cell Derived Exosomes as a Potent Vaccine Platform Targeting Primary Brain Cancers and Brain Metastases
• Current landscape and future directions of targeted-alpha-therapy for glioblastoma treatment
• Effects of Amphidinium carterae Phytocompounds on Proliferation and the Epithelial-Mesenchymal Transition Process in T98G Glioblastoma Cells
• Periostin-mediated activation of NF-kappaB signaling promotes tumor progression and chemoresistance in glioblastoma
• In vitro cellular and molecular plus in silico studies of a substituted bipyridine-coordinated Zn(II) ion: cytotoxicity, ROS-induced apoptosis, anti-metastasis, and BAX/BCL2 genes expression
• FDX1 Regulates the Phosphorylation of ATM, DNA-PKcs Akt, and EGFR and Affects Radioresistance Under Severe Hypoxia in the Glioblastoma Cell Line T98G
• Engineering Tumor-Specific Nanotheranostic Agent with MR Image-Guided NIR-II & -III Photodynamic Therapy to Combat Against Deeply Seated Orthotopic Glioblastoma
• Structure-Based Discovery Targeting GSK-3alpha Reveals Potent Nanomolar Selective 4-Phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine Inhibitor with Promising Glioblastoma and CNS-Active Potential in Cellular Models

Targeted Alpha Therapy (TAT) is an emerging and promising strategy that leverages Alpha Emitter radionuclides attached to tumor-targeting vectors to selectively destroy glioblastoma cells with minimal damage to surrounding healthy brain tissue.

• TAT uses alpha-emitting isotopes (e.g., ^213Bi, ^225Ac, ^211At) bound to molecules (antibodies, peptides) that selectively bind to receptors or antigens overexpressed on GB cells.
• Alpha particles travel only 50–100 micrometers, delivering highly cytotoxic, localized radiation that induces double-strand DNA breaks.
• This leads to apoptosis or necrosis of tumor cells, even in hypoxic or radioresistant regions.

• Clinical trials in GB patients using agents like ^213Bi-DOTA-substance P have demonstrated:
  1. Median progression-free survival: ~5.8 months
  2. Median overall survival: ~16.4 months
• Delivery routes include intratumoral or intracavitary administration, bypassing the blood-brain barrier.

• Bismuth-213 (^213Bi) – short half-life, ideal for localized treatment
• Actinium-225 (^225Ac) – long half-life, emits multiple alpha particles per decay chain
• Astatine-211 (^211At) – potential for systemic or localized use

• Precise tumor cell targeting with minimal off-target damage
• Effective against microscopic residual disease and tumor stem-like cells
• Suitable for recurrent or inoperable GB

• Tumor heterogeneity and limited targetable antigens
• Radionuclide production and supply
• Delivery across the blood-brain barrier
• Toxicity management (especially nephrotoxicity and hematotoxicity)

• Development of new ligands for better tumor targeting
• Improved radionuclide delivery systems, including nanoparticles and BBB-penetrant vectors
• Combination therapies (e.g., TAT + immunotherapy)
• Better stratification of patients through biomarkers and molecular profiling

• Roncali L, Hindré F, Samarut E, et al. *Current landscape and future directions of targeted-alpha-therapy for glioblastoma treatment*. Theranostics. 2025;15(11):4861-4889. doi:10.7150/thno.106081. PubMed Central

The 2025 narrative review article by Roncali et al., titled *“Current Landscape and Future Directions of Targeted-Alpha-Therapy for Glioblastoma Treatment“* and published in *Theranostics* ¹⁾ , offers a comprehensive examination of the advancements and challenges in employing targeted alpha therapy (TAT) for glioblastoma treatment. Given GB's notorious resistance to conventional therapies and its aggressive nature, this review is both timely and pertinent.

Strengths of the Review:

1. Comprehensive Scope: The authors meticulously collate data from various preclinical and clinical studies, providing readers with a broad understanding of TAT's current status in GB treatment. They discuss multiple alpha-emitting radionuclides, including ^213Bi, ^225Ac, and ^211At, highlighting their potential and limitations. ([Current landscape and future directions of targeted-alpha-therapy …](https://pmc.ncbi.nlm.nih.gov/articles/PMC12036880/?utm_source=chatgpt.com))

2. Clinical Insights: By analyzing clinical trials, such as those involving ^213Bi-DOTA-substance P, the review underscores TAT's safety and feasibility. For instance, a study reported a median progression-free survival of 5.8 months and a median overall survival of 16.4 months from treatment injection, suggesting potential benefits over traditional therapies. ([Targeted Alpha Therapy for Glioblastoma: Review on In Vitro, In …](https://pmc.ncbi.nlm.nih.gov/articles/PMC11230998/?utm_source=chatgpt.com), [Current landscape and future directions of targeted-alpha-therapy …](https://pmc.ncbi.nlm.nih.gov/articles/PMC12036880/?utm_source=chatgpt.com))

3. Identification of Challenges: The review does not shy away from discussing the hurdles facing TAT, such as the heterogeneity in therapeutic designs, the complexity of GB's tumor microenvironment, and the challenges in delivering radionuclides across the blood-brain barrier.

Areas for Improvement:

1. Depth of Critical Analysis: While the review is comprehensive, it could benefit from a more critical evaluation of the studies discussed. For example, a deeper analysis of the methodologies and potential biases in the cited clinical trials would provide readers with a clearer understanding of the data's robustness.

2. Comparative Analysis: The review could enhance its impact by comparing TAT's efficacy and safety profiles with other emerging therapies for GB, such as immunotherapies or targeted molecular treatments. This would position TAT within the broader landscape of GB treatment options.

3. Future Directions: While the title suggests a focus on future directions, the review could offer more concrete recommendations for upcoming research, such as specific targets for radionuclide conjugation or strategies to overcome delivery challenges.

Conclusion:

Roncali et al.'s review serves as a valuable resource for researchers and clinicians interested in the potential of TAT for GB treatment. Its comprehensive nature provides a solid foundation for understanding the current landscape. However, incorporating more critical analyses and comparative discussions would enhance its utility in guiding future research and clinical applications.