Tumour genomic analyses for individualised therapies for children with solid tumours.
The main research focus of the tumour biology working group lies on providing a well-founded scientific basis for therapy individualisation for children and adolescents with solid tumours. Today, the individualised adaptation of therapies to the respective tumour type is frequently based on the detection of genomic alterations of the tumour cells. Not only do genomic data provide valuable information on the molecular diagnosis, but also on the tumour’s aggressiveness, thus representing a valuable tool for therapeutic decisions. To enable the best possible and cost effective diagnostic system, we apply an ultra-high density SNParray (single nucleotide polymorphism) technique. Thus, tumour genomic analyses carried out by our group provide the attending doctor with the basis for choosing the best course of therapy. Minimal Residual Disease (MRD) monitoring for neuroblastoma patients.
The visualisation and quantification of disseminated tumour cells in the bone marrow, peripheral blood and aphaeretic products, performed with a fully automated microscope, enable the monitoring of the tumour burden during therapy and are thus further important tools to measure the response to cytotoxic or antibody (antiGD2) treatment. These studies are aimed at a better discrimination of tumours that respond to therapy from those that do not respond. It is expected that this information will enable doctors in the future to treat patients in an even more individualised way with greater chances for healing. Highest diagnosis quality through international cooperation.
In order to safeguard highest quality standards for examinations and put research findings into practice, international cooperation is indispensable for us, as, for example, our work with the INRG, the International Neuroblastoma Risk Group, which already resulted in 11 highly ranked internationally well recognized publications, helps to better stratify patients according to their biological tumour properties. In addition, we have been in charge of the European working group, the so-called SIOPEN biologists’ group (International Society of Paediatric Oncology European Neuroblastoma Research Network). The task area of this working group comprises the establishment of new factors for prognosis, the adaptation and development of new methods as well as quality assurance. Tumour cell senescence as a new strategy for therapy of highly aggressive neuroblastomas.
Another research focus of our working group concerns the treatment of highly aggressive neuroblastomas. Neuroblastoma is one of the most common tumours in infancy and early childhood. While infants with neuroblastoma usually have an excellent survival rate, the prognosis for children over 1.5 years, however, is not as good (except for localized maturing neuroblastomas). Our innovative therapeutic approach consists of exploiting the positive effect of tumour cell senescence. Tumour cell senescence arrests further uncontrolled tumour growth and, like apoptosis and necrosis, ultimately leads to tumour cell death and/or possibly to recognition and removal by the immune system which could thus become sensitized against the tumour cells. In previous research, we were able to show that in those neuroblastomas that are among the most aggressive ones due to an amplification of the MYCN oncogene, tumour cell aging (senescence) can be induced. This way, tumours lose their malignant properties. Currently, we are experimenting with in vitro and in vivo systems in order to comprehensively analyse the effects of tumour cell aging. Furthermore, we are working on the most efficient methods for letting tumour cells “age” (senescence induction).
Genomic features of paediatric tumours. Since 2012 our group has utilized an ultra-high density (UHD) SNParray method in order to gain the most comprehensive and detailed data on tumour genome aberrations currently achievable by array techniques. Using UHD SNP arrays, we can actually detect all genomic aberrations seen in paediatric tumours associated with gains and losses of genomic material down to the gene level (including presence or absence of heterozygosity and copy neutral homozygosities). Thus, a number of so far unknown aberrations show up in paediatric tumours. Together with the classical interphase in situ hybridization (I-FISH),this technique is applied to all types of solid tumours in children and young adults with special emphasis on neuroblastomas, Wilms’ tumours and Ewing tumours. Furthermore, presence of integrated/episomal viral copies (e.g. EBV, AdV and HHV6) is analysed by the FISH technique and quantified with an automatic microscope (Metafer, MetaSystems, Germany). Unambiguous identification and quantification of disseminated tumour cells in bone marrow, peripheral blood and aphaeretic samples is crucial to learn about the disease status of tumour patients. This analysis, routinely done on all neuroblastoma and rhabdomyosarcoma patients in Austria and a large number of patients enrolled in European clinical studies is facilitated by using the Automatic Immunofluorescence Plus FISH (AIPF) method (RCDetect, MetaCyte, MetaSystems, Germany), a technique also developed by our group.
Brunner C, Brunner-Herglotz B, Ziegler A, Frech C, Amann G, Ladenstein R, Ambros IM, Ambros PF
.(2016) Tumor Touch Imprints as Source for Whole Genome Analysis of Neuroblastoma Tumors.
PLoS One. 11(8):e0161369. doi: 10.1371/journal.pone.0161369. Weiss T, Taschner-Mandl S, Bileck A, Slany A, Kromp F, Rifatbegovic F, Frech C, Windhager R, Kitzinger H, Tzou CH, Ambros PF
, Gerner C, Ambros IM.(2016) Proteomics and transcriptomics of peripheral nerve tissue and cells unravel new aspects of the human Schwann cell repair phenotype.
Glia. doi: 10.1002/glia.23045. [Epub ahead of print] Taschner-Mandl S, Schwarz M, Blaha J, Kauer M, Kromp F, Frank N, Rifatbegovic F, Weiss T, Ladenstein R, Hohenegger M, Ambros IM, Ambros PF
. (2016) Metronomic topotecan impedes tumor growth of MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy induced senescence.
Oncotarget. 7(3):3571-86. doi: 10.18632/oncotarget.6527. Chagtai T, Zill C, Dainese L, Wegert J, Savola S, Popov S, Mifsud W, Vujanić G, Sebire N, Le Bouc Y, Ambros PF
, Kager L, O'Sullivan MJ, Blaise A, Bergeron C, Mengelbier LH, Gisselsson D, Kool M, Tytgat GA, van den Heuvel-Eibrink MM, Graf N, van Tinteren H, Coulomb A, Gessler M, Williams RD, Pritchard-Jones K. (2016) Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: A SIOP Renal Tumours Biology Consortium Study.
J Clin Oncol. pii: JCO660001. [Epub ahead of print] Thompson D, Vo KT, London WB, Fischer M, Ambros PF
, Nakagawara A, Brodeur GM, Matthay KK, DuBois SG. (2016) Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project.
Cancer.122(6):935-45. doi: 10.1002/cncr.29848. Epub 2015 Dec 28.