The rationale behind the approach rests on a striking biological quirk. Although prostate-specific membrane antigen, or PSMA, takes its name from the prostate, it is also expressed on the neovasculature of many solid tumors, including glioblastoma. The rapidly growing blood vessels that feed these tumors display the protein at high density, while normal brain vasculature largely does not. This creates a therapeutic window: a radioligand that homes in on PSMA can deliver cytotoxic radiation to the tumor’s own blood supply, starving it from within while sparing healthy tissue. Previous work by Wernicke and colleagues established PSMA as a vascular target in glioblastoma, and multicenter imaging studies have since confirmed that PSMA-targeted PET tracers accumulate in a substantial proportion of high-grade gliomas, making the antigen both an imaging biomarker and a candidate therapeutic target.

Actinium-225 is among the most potent radionuclides available to nuclear medicine. It decays through a cascade of four alpha emissions, each depositing enormous energy over distances of only a few cell diameters. This dense, short-range radiation causes clusters of irreparable double-strand DNA breaks, killing targeted cells and even neighboring tumor cells through a bystander effect, regardless of oxygenation or cell-cycle status, factors that often blunt the effectiveness of conventional photon radiotherapy. The same short particle range, however, demands that the radionuclide be delivered with precision, which is precisely what the PSMA-targeting ligand is designed to achieve. In prostate cancer, [²²⁵Ac]-PSMA-617 has produced dramatic responses, but extending this technology to brain tumors required evidence that the ligand would actually localize to glioma tissue in patients.

To test the concept, the researchers treated four patients with histologically confirmed recurrent high-grade glioma: three with glioblastoma and one with a WHO grade III high-grade diffuse glial tumor. Each patient received [²²⁵Ac]-PSMA intravenously at a dose of 100 kilobecquerels per kilogram of body weight per cycle, with treatment cycles intended at intervals of eight to twelve weeks. Before therapy, all patients underwent PSMA-targeted PET imaging with either [⁶⁸Ga]-PSMA PET/MRI or PET/CT, combined with contrast-enhanced magnetic resonance imaging, to identify PSMA-avid index lesions. Baseline and follow-up assessments were performed visually and then quantified using semi-quantitative parameters on the hybrid imaging studies, while clinical status and hematologic parameters were monitored throughout therapy and follow-up.

The imaging results offered cautious grounds for optimism. Although every patient ultimately developed progressive disease, the predefined PSMA-avid index lesion regressed in one patient and remained stable in another. In a disease where progression is typically rapid and relentless, any evidence of local disease control is noteworthy, particularly with a first-in-kind systemic therapy delivered on an outpatient basis. The investigators emphasize that the study was designed to assess feasibility, safety, and preliminary efficacy rather than survival outcomes, and the small cohort of four patients means that no firm conclusions about efficacy can yet be drawn. Nevertheless, the observation that a radiopharmaceutical could produce measurable tumor control in heavily pretreated brain tumor patients represents a proof of principle for the entire strategy.

Safety findings were equally encouraging. No grade three or higher adverse events attributable to [²²⁵Ac]-PSMA were observed, and there were no treatment-related deaths. The toxicity that did occur was limited and low-grade, consisting mainly of mild xerostomia, or dry mouth, a well-known consequence of PSMA-targeted radioligand therapy caused by PSMA expression in the salivary glands. This favorable tolerability profile is significant because patients with recurrent glioma have often already endured intensive radiation and chemotherapy, leaving limited reserve for additional myelosuppressive treatment. The absence of hematologic toxicity in this small series suggests that the 100 kBq/kg dose level can be delivered safely, though the authors caution that larger cohorts are needed to characterize the full toxicity profile.

The theranostic framework underlying the trial deserves particular attention. Theranostics pairs a diagnostic imaging agent with a therapeutic compound sharing the same molecular target, allowing clinicians to confirm target expression before committing a patient to treatment. In this study, [⁶⁸Ga]-PSMA PET served as the companion diagnostic, identifying which lesions expressed PSMA on their vasculature and would therefore be expected to accumulate the alpha-emitting therapeutic. This personalized selection process, now standard in prostate cancer radioligand therapy following the success of lutetium-177 PSMA-617, could in principle spare glioma patients from ineffective treatment while concentrating clinical trials on the subset of tumors most likely to respond.

Significant hurdles remain before this approach can move toward routine clinical use. Alpha-emitting radiopharmaceuticals pose unique challenges, including the global scarcity of actinium-225, which is produced in limited quantities at only a handful of accelerator facilities worldwide, a constraint documented in recent mapping studies of global alpha-emitter production. The decay daughters of actinium-225 can also break free from their chelator and redistribute to normal organs, particularly the kidneys and salivary glands, a phenomenon that preclinical dosimetry studies are actively working to quantify and mitigate. Delivery to brain tumors is further complicated by the blood-brain barrier, although the vascular targeting strategy may partially circumvent this obstacle because the tumor neovasculature lies on the accessible side of the barrier. Optimal dose, cycle number, and combination with other therapies all remain to be defined.

Earlier targeted alpha therapy studies in glioma, including trials of actinium-225 and bismuth-213 labeled substance P analogues delivered directly into resection cavities, have demonstrated that alpha radiation can achieve long-term tumor control in selected patients, and reports of durable responses in low-grade gliomas have fueled interest in expanding these approaches. The present study extends the concept to systemic administration, which is far simpler logistically and could theoretically address both the primary lesion and distant tumor satellites. The Istanbul team, which received no external funding for the work and declared no competing interests, conducted the study with institutional ethics approval and informed consent from all participants, in accordance with the Declaration of Helsinki.

For now, the message from this pilot experience is one of measured hope. Systemic [²²⁵Ac]-PSMA therapy appeared feasible and well tolerated in patients who had exhausted conventional options, and it produced preliminary evidence of disease control in PSMA-expressing recurrent high-grade glioma. The authors and observers of the field alike stress that these findings must be validated in larger, controlled studies with longer follow-up before any claims of clinical benefit can be made. Yet the convergence of several trends, including expanding global production of actinium-225, improving PSMA PET imaging of brain tumors, and growing clinical experience with alpha radioligand therapy, suggests that targeted alpha therapy may be poised to become a genuine new frontier in the treatment of one of medicine’s most lethal cancers. If subsequent trials confirm and extend these early signals, the theranostic pairing of PSMA imaging with alpha-emitting therapy could offer patients with recurrent glioma something they have rarely had: a precisely targeted, systemically deliverable option with real potential to alter the course of their disease.

Subject of Research: Systemic targeted alpha therapy using actinium-225 labeled PSMA radioligand for recurrent high-grade glioma

Article Title: Targeted alpha therapy for recurrent high-grade glioma with [²²⁵Ac]-PSMA: a new theranostic approach

Article References: Sayman, H. B., Aras, O., Hekim, M. V., Sağlam, K., Akgün, E., & Dinçbaş, F. Ö. (2026). Targeted alpha therapy for recurrent high-grade glioma with [²²⁵Ac]-PSMA: a new theranostic approach. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08194-6

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08194-6

Keywords: glioblastoma, high-grade glioma, targeted alpha therapy, actinium-225, PSMA, theranostics, radioligand therapy, PET imaging, recurrent brain tumor, nuclear medicine, alpha emitters, PSMA-targeted therapy