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Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment.

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed hClpP to be identified as its main target. The hyperactivation of hClpP causes damage to mitochondrial oxidative phosphorylation and cell death. In some DIPG patients receiving ONC201, an acquired resistance was observed. In this context, a wide program was initiated to discover original scaffolds for new hClpP activators to treat ONC201-non-responding patients. Harmaline, a small molecule belonging to the chemical class of β-carboline, was identified through Fingerprints for Ligands and Proteins (FLAP), a structure-based virtual screening approach. Molecular dynamics simulations and a deep in vitro investigation showed interesting information on the interaction and activation of hClpP by harmaline.

SUBMITTER: Miciaccia M

PROVIDER: S-EPMC10821046 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment.

Miciaccia Morena M Rizzo Francesca F Centonze Antonella A Cavallaro Gianfranco G Contino Marialessandra M Armenise Domenico D Baldelli Olga Maria OM Solidoro Roberta R Ferorelli Savina S Scarcia Pasquale P Agrimi Gennaro G Zingales Veronica V Cimetta Elisa E Ronsisvalle Simone S Sipala Federica Maria FM Polosa Paola Loguercio PL Fortuna Cosimo Gianluca CG Perrone Maria Grazia MG Scilimati Antonio A

Pharmaceuticals (Basel, Switzerland) 20240119 1

Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. <i>In silico</i> and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crysta ...[more]

PMID: 38276008

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Project description:BackgroundDiffuse intrinsic pontine glioma (DIPG) is a fatal disease with a median overall survival (OS) of less than 12 months after diagnosis. Radiotherapy (RT) still remains the mainstay treatment. Several other therapeutic strategies have been attempted in the last years without a significant effect on OS. Although radiological imaging is the gold standard for DIPG diagnosis, the urgent need to improve the survival has led to the reconsideration of biopsy with the aim to better understand the molecular profile of DIPG and support personalized treatment.MethodsIn this study, we present a single-center experience in treating DIPG patients at disease progression combining targeted therapies with standard of care. Biopsy was proposed to all patients at diagnosis or disease progression. First-line treatment included RT and nimotuzumab/vinorelbine or temozolomide. Immunohistochemistry-targeted research included study of mTOR/p-mTOR pathway and BRAFv600E. Molecular analyses included polymerase chain reaction, followed by Sanger sequences and/or next-generation sequencing.ResultsBased on the molecular profile, targeted therapy was administered in 9 out of 25 patients, while the remaining 16 patients were treated with standard of care. Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (5/9), PI3K/AKT/mTOR pathway and BRAFv600E (1/9), ACVR1 (2/9) and PDGFRA (1/9); no severe side effects were reported during treatment. Response to treatment was evaluated according to Response Assessment in Pediatric Neuro-Oncology criteria, and the overall response rate within the cohort was 66%. Patients treated with targeted therapies were compared with the control cohort of 16 patients. Clinical and pathological characteristics of the two cohorts were homogeneous. Median OS in the personalized treatment and control cohort was 20.26 and 14.18 months, respectively (p = 0.032). In our experience, the treatment associated with the best OS was everolimus.ConclusionDespite the small simple size of our study, our data suggest a prognostic advantage and a safe profile of targeted therapies in DIPG patients, and we strongly advocate to reconsider the role of biopsy for these patients.

Dataset Information

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment.

Publications

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment.

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