A New Treatment Opportunity for DIPG and Diffuse Midline Gliomas: 5-ALA Augmented Irradiation, the 5aai Regimen

Abstract

Prognosis for diffuse intrinsic pontine glioma (DIPG) and generally for diffuse midline gliomas (DMG) has only marginally improved over the last ~40 years despite dozens of chemotherapy and other therapeutic trials. The prognosis remains invariably fatal. We present here the rationale for a planned study of adding 5-aminolevulinic acid (5-ALA) to the current irradiation of DIPG or DMG: the 5aai regimen. In a series of recent papers, oral 5-ALA was shown to enhance standard therapeutic ionizing irradiation. 5-ALA is currently used in glioblastoma surgery to enable demarcation of overt tumor margins by virtue of selective uptake of 5-ALA by neoplastic cells and selective conversion to protoporphyrin IX (PpIX), which fluoresces after excitation by 410 nm (blue) light. 5-ALA is also useful in treating glioblastomas by virtue of PpIX’s transfer of energy to O2 molecules, producing a singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective malignant cell cytotoxicity. This is called photodynamic treatment (PDT). Shallow penetration of light required for PpIX excitation and resultant energy transfer to O2 and cytotoxicity results in the inaccessibility of central structures like the pons or thalamus to sufficient light. The recent demonstration that keV and MeV photons can also excite PpIX and generate singlet O2 allows for reconsideration of 5-ALA PDT for treating DMG and DIPG. 5-ALA has an eminently benign side effect profile in adults and children. A pilot study in DIPG/DMG of slow uptitration of 5-ALA prior to each standard irradiation session—the 5aai regimen—is warranted.

DNA Strand Break Properties of Protoporphyrin IX by X-ray Irradiation against Melanoma

“…Microarray analysis of tumor tissues following 5-ALA and X-ray treatment showed that GO terms, including 'immune response' and 'defense response', and genes related to MHC class I were slightly up-regulated in the X-ray treatment group and highly up-regulated in the 5-ALA and X-ray treatment group [6]. Thus, RDT with 5-ALA is expected to stimulate the immune system more than RT alone and has the potential to further our efforts to "harness synergistic biology between radiation and immunotherapy" [23].…”

“…PpIX has the ability of ROS generation under X-ray irradiation [22]. However, a robust physics-based explanation for the 5-ALA-PpIX radiosensitizing effect is currently lacking [23]. One of the characteristics of PpIX as a photosensitizer is its ability to undergo photobleaching [24,25].…”

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting

“…A prerequisite for sonodynamic therapy to be effective is, of course, evidence that the sonosensitizer accumulates in tumor cells. It has been widely demonstrated that 5-ALA has preferential uptake in gliomas [37] , pediatric brain tumors [38 , 39] , and DIPG [40] . At the FUSF DIPG workshop, Dr. Javad Nazarian's team shared that not only does 5-ALA, an FDA approved sonosensitizer, accumulate in higher amounts in DMG cells compared to C6 rat glioma models, but also that the DMG cells retain the 5-ALA and produce PpIX for longer amounts of time [13] .…”

Systematic Review of Photodynamic Therapy in Gliomas

“…Although all of the aforementioned studies on PDT efficacy have been performed on adult CNS tumors, pre-clinical and clinical studies have also been performed evaluating the performance of PDT in pediatric brain tumors via second-generation PSs such as 5-ALA and TS [217][218][219]. One of the most recent reports evaluating PDT feasibility for malignant pediatric brain tumors has reported on treatment using TS in children and young adolescents with brain tumors, including diffuse midline glioma (DMG), glioblastoma, and high-grade glioma.…”