Theranostic Uses of the Heme Pathway in Neuro-Oncology: Protoporphyrin IX (PpIX) and Its Journey from Photodynamic Therapy (PDT) through Photodynamic Diagnosis (PDD) to Sonodynamic Therapy (SDT)
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. The Heme Pathway—Introducing PpIX
1.2. Erythropoietic Protoporphyria (EPP): Nature’s Experiment in Photodynamic Phototoxicity and Its Use as a Model for ALA PDT
2. The Beginning of PpIX Therapeutics—Topical ALA PDT: From Red Light to Blue Light
2.1. PpIX Photodynamic Diagnosis (PDD)—The Next Step in the Evolution toward Sonodynamic Therapy
2.2. Interstitial ALA PDT (iPDT) for the Treatment of Recurrent Glioblastomas (rGBMs)
3. From PDT to SDT—Preclinical Studies in Rodent Models on SDT for Malignant Gliomas
3.1. Optimization of Single-Treatment ALA SDT in a C6 Rat Glioma Has Positive Effects on Survival
3.2. DIPG (DMG) Tissue Culture Cells Accumulate PpIX When Exposed to Exogenous ALA
4. Current SDT Clinical Trials
4.1. First-in-Man Phase 0/1 Clinical Trial of SDT
4.2. Ongoing Phase 1/2 Clinical Trials of ALA SDT for Malignant Glioma
4.3. First-in-Child Pediatric SDT Trial for Diffuse Intrinsic Pontine Glioma (DIPG)
5. Likely Regulatory Path for US Commercial Clinical Development of ALA iPDT and ALA SDT in Neuro-Oncology: Potential Barriers
5.1. SDT: Suggestions for Commercial Clinical Development in the Treatment of Gliomas
- In the US, the drug label will likely carry sonication treatment methods.
- Clearly define device frequency, power, the nature of and frequency of pulses, and some acoustic parameter(s) as well as total energy delivered.
- Determine, with the FDA, the type of sonication parameters required for inclusion in the label and standardize those parameters across SDT clinical trials, regardless of the type of device used to produce ultrasound energies.
5.2. Future Research—Elucidating the Short-Term and Long-Term Cellular Effects of ALA iPDT and ALA SDT on Malignant Gliomas: How Many Ways Can You Kill a Cell?
6. Conclusions and Future Directions in the Evolution of and Research into Clinical SDT
6.1. Future Directions in the Evolution of Clinical SDT—How Clinical Indications and Use Will Be Determined by the Type of Device Used to Produce PpIX-Activating Ultrasound
6.1.1. Diffusely Targeting Large Brain Areas for SDT (Alpheus Medical)
6.1.2. SDT Using a Neuronavigation-Guided Device (Navifus Device)
6.1.3. MRgFUS—Using ALA SDT as a Neurosurgical Tool
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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NCT Number | Study Title | Condition | Description | Treatment | Endpoints |
---|---|---|---|---|---|
NCT06039709 | Sonodynamic Therapy in Patients with Recurrent GBM | rGBM | Phase 1, single center | Single treatment of oral 5-ALA with Neuronavigation-guided LIFU (NaviFUS), 1–3 weeks before surgery | Safety, biomarker analysis |
NCT04845919 | Sonodynamic Therapy with ExAblate System in GBM Patients (Sonic ALA) | GBM | Phase 2, single center | Single treatment of oral 5-ALA with MRgFUS (Exablate), followed by surgery 15–21 days post SDT | Safety, biomarker analysis |
NCT04559685 | Study of Sonodynamic Therapy in Participants with Recurrent HGG | HGG | Phase 0, single center | Single treatment of IV ALA (SONALA-001) with MRgFUS (Exablate), followed by surgery 4–6 days post SDT | Safety, biomarker analysis, immune profiling |
NCT05362409 | Study to Evaluate 5-ALA Combined with CV01 Delivery of Ultrasound in Recurrent HGG | HGG | Phase 1, multicenter | Monthly treatment with oral ALA with CV01 ultrasound | Safety, determination of Maximum Tolerable Duration of Sonication (MTDu) |
NCT05370508 | A Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Subjects with Recurrent GBM | rGBM | Phase 1/2, multicenter | Monthly treatments of IV ALA (SONALA-001) with MRgFUS (Exablate) device | Safety and tolerability, determination of MTD and RP2D |
NCT05123534 | A Phase 2 Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Patients With DIPG | DIPG | Phase 1/2, multicenter | Monthly treatments of IV ALA (SONALA-001) with MRgFUS (Exablate) device | Safety and tolerability, determination of MTD and RP2D |
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Marcus, S.L.; de Souza, M.P. Theranostic Uses of the Heme Pathway in Neuro-Oncology: Protoporphyrin IX (PpIX) and Its Journey from Photodynamic Therapy (PDT) through Photodynamic Diagnosis (PDD) to Sonodynamic Therapy (SDT). Cancers 2024, 16, 740. https://doi.org/10.3390/cancers16040740
Marcus SL, de Souza MP. Theranostic Uses of the Heme Pathway in Neuro-Oncology: Protoporphyrin IX (PpIX) and Its Journey from Photodynamic Therapy (PDT) through Photodynamic Diagnosis (PDD) to Sonodynamic Therapy (SDT). Cancers. 2024; 16(4):740. https://doi.org/10.3390/cancers16040740
Chicago/Turabian StyleMarcus, Stuart L., and Mark P. de Souza. 2024. "Theranostic Uses of the Heme Pathway in Neuro-Oncology: Protoporphyrin IX (PpIX) and Its Journey from Photodynamic Therapy (PDT) through Photodynamic Diagnosis (PDD) to Sonodynamic Therapy (SDT)" Cancers 16, no. 4: 740. https://doi.org/10.3390/cancers16040740
APA StyleMarcus, S. L., & de Souza, M. P. (2024). Theranostic Uses of the Heme Pathway in Neuro-Oncology: Protoporphyrin IX (PpIX) and Its Journey from Photodynamic Therapy (PDT) through Photodynamic Diagnosis (PDD) to Sonodynamic Therapy (SDT). Cancers, 16(4), 740. https://doi.org/10.3390/cancers16040740