Experimental Local Therapy in High-Risk Neuroblastoma

• Applicant: Dr. Janina Fischer
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442640712

The prognosis of patients with high-risk-neuroblastoma still is unfavorable despite multimodal treatment. Untreated high-risk-neuroblastoma analyzed by whole-genome sequencing showed the diverse mutation spectrum. It revealed new recurrent rearrangements of the telomerase reverse transcriptase gene (TERT) and the well-known gene alterations (like MYCN and ALK). The clinical course of patients with TERT rearrangements or MYCN amplifications are both associated with a poorer outcome in contrast to patients without aberration. If a high TERT expression (by TERT rearrangements or by MYCN amplification) occurs in combination with a p53/RAS pathway mutation (for example ALK mutation), patients are defined as ultra-high-risk-patients. This group has an even worse prognosis than the high-risk-group.The treatment with telomerase inhibitors Imetelstat and 6-thio-dG showed a reduced tumor volume and a better survival of animals harboring tumors with a TERT rearrangement. In MYCN amplified tumors, this effect could not be seen in vivo. Thus, it is necessary to elucidate if tumors with MYCN amplification (with or without ALK mutation) show a better response to a local application of telomerase inhibitors by a silk waiver and a tripled dosage. This will be incorporated at the resective surgery of the primary adrenal tumor located. Furthermore, we analyze telomerase activity, proliferation, apoptotic potential and DNA damage of the treated tumors.Experiments with potential new therapeutic agents will be essential for the development of individualized treatment strategies in high-risk-neuroblastoma.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Bill Chiu, Ph.D.