DIPG-30. A NEW TREATMENT OPPORTUNITY FOR DIPG: 5-ALA AND SONODYNAMIC AUGMENTED MEV IRRADIATION, THE ASAI PROTOCOL

Abstract

Prognosis for diffuse intrinsic pontine glioma [DIPG] has only marginally improved over the last ∼40 years despite dozens of chemotherapy trials. We present the rationale for adding 5-aminolevulinic acid [5-ALA] to current palliative irradiation of DIPG, plus doxycycline and unfocused 1 MHz ultrasound, the ASAI Regimen. 5-ALA enhances meV radiation of gliomas. 5-ALA is currently used in intraoperative demarcation of overt glioblastoma margins by virtue of glioblastoma cells' selective uptake of 5-ALA and selective conversion to protoporphyrin IX [PpIX], a fluorescent molecule. 5-ALA is also useful in treating gliomas by virtue of PpIX's emission of a photon that creates singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective cancer cell cytotoxicity after illumination with 410 nm [blue] light. Shallow penetration of excitation light required for PpIX generation of cytotoxicity, and inaccessibility of central structures like the pons or thalamus to blue light excitation lead to 5-ALA phototherapy not being considered for DIPG. But DIPGs selectively take up 5-ALA as do other gliomas and meV irradiation induced cytotoxicity also is enhanced by pre-irradiation oral 5-ALA. The old antibiotic doxycycline enhances glioma cell uptake of 5-ALA. Low power unfocused 1 MHz ultrasound, not neurotoxic or damaging to brain structures, augments 5-ALA glioma cell cytotoxicity. Both doxycycline and ultrasound are therefore added to ASAI Protocol. A pilot study of uptitration of oral 5-ALA plus doxycycline, and ultrasound delivered through a bone window prior to each standard palliative irradiation session-the ASAI Protocol-is warranted.