- Clinical studies in children with liver tumours
- miR-492 in hepatoblastoma
- AHR and DRD5 in AML with MLL-fusion gene
Primary childhood liver tumours encompass a range of differing entities whose incidence varies with age. The commonest tumour in young children are hepatoblastomas (43% of all liver tumours) followed by haemangioendotheliomas (13%) and then haemangiomas and mesenchymal hamartomas (6%). In contrast the most frequent type of liver tumour diagnosis in school aged children is hepatocellular carcinomas (HCC, 23%) followed by sarcomas (6%), focal nodular hyperplasia (2%), adenomas (2%) and other tumours (5%). The Registry for Liver Tumours in Children and Adolescents established by our team (1.1.2011) is the first registry to systematically collect informations not only on malignant, but also non-malignant liver tumours in the GPOH catchment area. This information is an invaluable data source for research into areas such as the epidemiology, pathology and therapeutic quality of liver tumour treatment (Health Care Provision Research) for all childhood liver tumours. Currently the PHITT study (Paediatric Hepatic International Tumour Trial) is established for children and adolescents with hepatoblastoma or hepatocellular carcinoma in Germany.
MiR-492 was demonstrated to be significantly upregulated in metastatic HB. Significant correlation of miR-492 levels with the CHIC-stratification system and the 16-gene-signature was also noted. Functionally, miR-492 triggers metastatic progression, perhaps by direct suppression of the cell surface glycoprotein, CD44 (von Frowein et al, Liver Int. 2018; von Frowein et al, Hepatology 2011). Thus, miR-492 has diagnostic, prognostic and therapeutic potential. The current question is, how does miRNA-492 affect the tumour environment thus promoting metastasis of the tumour from the liver to the lungs? The ultimate goal is to create an anti-miR therapy, which can be used in conjugation with conventional chemotherapy. . A further goal is the creation of liquid miRNA-492 biopsies.
Due to a still unfavorable prognosis, new, targeted therapies are urgently needed for Acute Myeloid Leukemia (AML). An MLL-fusion gene is present in the leukemic cells of a quarter of all children with AML. In preparatory studies, we could prioritize therapeutic targets downstream of the leukemogenic but hard-to-drug MLL-AF9 fusion gene. Two of these, the Aryl Hydrocarbon Receptor (AHR) and the Dopamine Receptor D5 (DRD5), have rarely been studied in the context of leukemia. Besides the recently described roles of AHR (pro-differentiational and anti-proliferative) and DRD5 (proproliferative and prognostic relevance in AML), we could provide evidence of pro-apoptotic and anti-proliferative effects of an AHR agonist and a DRD5 antagonist on leukemic cells with MLL-fusion. This project aims to elucidate the mode of action (signal transduction pathways) as well as the therapeutic efficacy and applicability of the two potential drug targets AHR and DRD5 in the context of AML. Due to the presence of well characterized receptor modulators, a fast transition into the clinic seems within reach.
Prof. Dr. med. Irene Schmid, Group Leader. Email: firstname.lastname@example.org. Tel: +49 89 4400 54499
Dr. rer. nat. Julia von Frowein, Postdoc. Email: email@example.com. Tel: +49 4400 57818
Dr. rer. nat. Katrin K. Fleischmann, Postdoc. Email: firstname.lastname@example.org. Tel: +49 4400 57818
Carola Laudano, Technician. Email: email@example.com. Tel: +49 4400 57818
Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P (2017). Lancet Oncol 18, 122-131.
Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Schmid I, Häberle B, Albert MH, Corbacioglu S, Fröhlich B, Graf N, Kammer B, Kontny U, Leuschner I, Scheel-Walter HG, Scheurlen W, Werner S, Wiesel T, von Schweinitz D (2012). Pediatr Blood Cancer 58, 539-544.
MiR-492 regulates metastatic properties of hepatoblastoma via CD44. Von Frowein J, Hauck SM, Kappler R, Pagel P, Fleischmann KK, Magg T, Cairo S, Roscher A, von Schweinitz D, Schmid I (2018). Liver Int 38, 1280-1291.
MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma. von Frowein J, Pagel P, Kappler R, von Schweinitz D, Roscher A, Schmid I (2011). Hepatology 53, 833-842.
The leukemogenic fusion gene MLL-AF9 alters microRNA expression pattern and inhibits monoblastic differentiation via miR-511 repression. Fleischmann KK, Pagel P, von Frowein J, Magg T, Roscher AA, Schmid I (2016). J Exp Clin Cancer Res 13, 35:39.
RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes. Fleischmann KK, Pagel P, Schmid I, Roscher AA (2014). Mol Cancer 11, 13-27.
Irene Schmid Group
Research Building, KU.07, Lindwurmstr. 2a, 80337 Munich, Germany
Dr. von Hauner Children`s Hospital, Department for Pediatric Hematology, Oncology, Stem Cell Transplantation, Lindwurmstr. 4, 80337 Munich
Tel. +49 89 4400 54499 or 57818
Fax. +49 89 4400 57514