Hematology / Oncology (Paediatrics)
Telomere Lengths in Pediatric Acute Lymphblastic Leukamia (ALL)
Shortened telomeres and high levels of telomerase activity are found in different cancers, as compared to normal cells.
Telomeres are repetitive non-coding nucleotide sequences capping the termini of linear chromosomes. They play a pivotal role in normal cell replication during which they get shorter and shorter.
A ribonucleoprotein complex, the so-called telomerase, protects telomeres from shortening by promoting their regeneration after cell division. Thus, cell proliferation capacity is greatly dependent on telomere length and telomerase function. High levels of telomerase activity probably allow leukemic cells to continuously replicate despite marked telomeric shortening. For childhood (ALL) and other pediatric malignancies, only very limited data on telomere lengths in different cell subsets is available. Telomere maintenance has become an important target of new therapies and recent studies show antiproliferative effects of genetic and pharmacological telomerase inhibition. In particular, Baerlocher and colleagues have shown that the telomerase inhibitor Imetelstat induces complete hematological remission in the majority of patients with Essential Thrombocythemia (ET).
In our study, the pilot phase of which is supported by “Grants-in-Aid” of the DBMR, we are planning to systematically determine telomere lengths from peripheral blood of pediatric patients with ALL at the Division of Paediatric Haematology / Oncology, Department of Paediatrics, Inselspital, Bern University Hospital. Measurements will be performed using multicolor flow-FISH system, a differentiated and sensitive method combining flow cytometry with fluorescence in situ hybridization, allowing analyses of distinct cell subpopulations. This method is established and, as part of a collaboration in this project, accessible in the laboratory of Professor Gabriela Baerlocher at the Inselspital, Bern University Hospital. In addition to measurements at time of diagnosis, we are going to determine telomere lengths and telomerase activity during therapy. This will give us the opportunity to correlate telomere lengths and telomerase activity with other laboratory and clinical parameters, i.e. response to therapy. A long-term goal of this study is to assess the in vitro antiproliferative effects of telomerase inhibition, to develop more targeted therapeutic approaches for pediatric ALL.
New therapeutic targets and innovative drug deliveries for pediatric solid tumors
Our aim is to improve existing therapies and devise novel therapies for pediatric solid tumors, with particular focus on rhabdomyosarcoma.
The treatment of tumors in children must meet specific needs, as chemotherapeutic agents can lead to significant long-term consequences. It is therefore the aim of our research to optimize existing therapies by targeting them to the tumor, sparing normal tissues.
One strategy is to decorate drug-loaded nanoparticles with molecules that promote tumor accumulation. We are developing approaches based on two well established technologies: liposomes and silica nanotubes. Liposomes are small lipid vesicles, approximately 100 nm in size. Silica nanotubes, are hollow tubes, 30 to 300 nm in length, with an inner diameter of 10-20 nm. Both liposomes and silica nanotubes can be loaded with chemotherapeutic agents.
One way to achieve tumor accumulation, is the identification of molecules which bind specifically to tumor cells and thus can concentrate therapeutic agents in the tumor tissue. Peptides or nanobodies that bind specifically to tumors, are a promising possibility. We will develop peptides or nanobodies that bind specifically to rhabdomyosarcoma, the most common soft tissue sarcoma in children. We have optimized the technology to decorate liposomes with these molecules. We are now selecting for the best molecules and will be establishing the optimal conditions to deliver chemotherapeutic drugs in pre-clinical models.
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