Matthias Fischer - A 2

The functional and therapeutic significance of activated telomerase in neuroblastoma

Abstract

Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system. While half of these tumors have an adverse clinical course despite intensive treatment, spontaneous regression occurs frequently in the remaining cases. We have recently discovered that activation of telomere maintenance mechanisms is a hallmark of high-risk neuroblastoma (Peifer et al., Nature 2015). In the most aggressive tumors, telomerase is activated by genomic TERT rearrangements or MYCN amplification. In the remaining high-risk cases, telomeres are stabilized by the Alternative Lengthening of Telomeres pathway. By contrast, low-risk tumors lack telomere maintenance mechanisms, presumably explaining their inability to gain immortal proliferation capacity.

We here aim to validate the functional significance of telomerase activation in neuroblastoma development and progression, and to determine whether telomerase can be exploited as a therapeutic target in this malignancy. We will examine two distinct genetically engineered mouse models to assess the role of telomerase activation in neuroblastoma pathogenesis: First, we will investigate whether tetracycline-inducible expression of a Tert transgene in neural-crest derived cells leads to neuroblastoma development. In a second model, we will examine whether telomerase inactivation impairs initiation and growth of MYCN-driven neuroblastoma. In addition, we will use in vitro and in vivo experiments to assess whether pharmacological telomerase inhibition alone or in rationale combinations may represent a valuable approach to target neuroblastoma.

Clinical/medical relevance and sustainability in disease understanding

Our recent genomic studies suggest that high-risk neuroblastoma is mechanistically defined by activation of telomere maintenance mechanisms. We here will substantiate the functional relevance of telomerase activation in high-risk neuroblastoma pathogenesis in vivo, and determine its potential significance as a therapeutic target in this deadly disease. Since telomerase is activated in most cancers, our efforts may also expand our knowledge on the role of telomerase in tumorigenesis in general.


Prof. Dr. med. Matthias Fischer

Dept. of Children and Adolescent Medicine

Prof. Dr. med. Matthias Fischer

Principal Investigator A 2

matthias.fischer@uk-koeln.de

Work +49 221 478 6816

University Children's Hospital
Kerpener Str. 62
50937 Cologne

Publications - Matthias Fischer

Link to PubMed