Use of targeted therapy in children from 3 to 18 years of age with the diagnosis of diffuse intrinsic pontine glioma-DIPG based on the results of DIPGen genetic tests

Multicenter open study of the use of targeted therapy in pediatric patients from 3 to 18 years of age with diagnosis of diffuse intrinsic pontine glioma (DIPG) based on genetic test results (Gen) - DIPGen. Diffuse infiltrating gliomas of the bridge constitute about 8-10% of all tumors of the central nervous system (CNS) in children. While there has been spectacular progress in the treatment of childhood cancers in recent decades, this does not apply to DIPG, where the median overall survival varies between 8 and 12 months. The cause of these failures should be associated with the location of the tumor, its infiltrating nature in eloquent areas of the brainstem, which makes it impossible to perform complete tumor resection. In addition, approximately 80% of patients are diagnosed with high-grade gliomas, which undoubtedly have a negative impact on survival. The mainstay of DIPG treatment is radiation therapy. Numerous clinical trials have not shown a significant benefit from the use of chemotherapy, leaving irradiation as the only treatment option for these patients.

Moreover, due to the neurological condition of patients and the risk of its deterioration after neurosurgical interventions, with the simultaneous lack of influence of the obtained pathomorphological examination of the tumor on the patient's treatment and its survival, until recently, biopsies of this type of tumors have not been routinely performed. Hence the lack of comprehensive knowledge about the molecular properties of these tumors in children. In the last decade, the development of molecular research in human neoplasms has contributed to the development of new effective targeted therapies and improved treatment outcomes in selected neoplasms. Therefore, such solutions should be sought in children with DIPG. Identification of biomarkers, including molecular changes differentiating neoplasms with similar histological features, prognostic and prognostic markers, and molecular targets will allow for correct diagnosis, prognosis of neoplastic disease and optimization of its treatment by introducing targeted therapies. As a result, improvement in treatment outcomes in this group of patients is expected.

The project envisages a standardized diagnostic and therapeutic procedure in approximately 100 children with DIPG.

MRI scans will be performed for each patient included in the project, followed by a tumor biopsy to establish a histopathological diagnosis and identify significant molecular markers.

Molecular analysis will be carried out with the use of NGS (Next Generation Sequencing) technology at the DNA and RNA level through Whole Exome Sequencing (WES) and with the use of targeted panels (identification of gene fusions). Both the genetic material from the neoplastic tissue and the reference material from the patient's peripheral blood lymphocytes will be analyzed. The research will be conducted in two ways. In the first stage, molecular changes will be identified that will enable patients to be included in the therapeutic groups selected in the project (Annex 3). The aim of the second stage of molecular research will be to determine the full molecular profile of DIPG and to identify possible new, important therapeutic targets.

Following biopsy, patients will be scheduled for irradiation according to standard DIPG treatment. All patients will receive sirolimus during radiotherapy. Research conducted at the National Cancer Institute has shown that Rapamycin inhibits the proliferation of cells of various types of human tumors, including gliomas, and studies are currently being conducted using this medicinal product in selected diseases. The above facts justify the inclusion of sirolimus in the treatment of DIPG. Further systemic treatment will be determined based on the identified molecular targets with medicinal products licensed for other indications, which in preclinical or clinical studies show an inhibitory effect on the development of glioblastoma (sirolimus vs sirolimus in combination with trametinib).

The project is of innovative, cognitive and applied nature.

Until now, in Poland, no regular molecular tests have been conducted in children with DIPG. The number of patients planned in the project will ensure the credibility of the results and will contribute to broadening the knowledge in this field. We expect that the introduction of targeted therapies will improve treatment outcomes in the form of prolonged progression-free and overall survival, as well as improve the quality of life of patients. Assessment of the complete molecular profile may reveal new therapeutic targets for this patient group.