Project Details
Projekt
A novel preclinical orthotopic-humanised osteosarcoma model - Creating a tissue engineered orthotopic humanised in vivo microenvironment for translational osteosarcoma research in respect to drug testing and new prognostic biomolecular markers
Applicant
Dr. Ferdinand Wagner
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
from 2014 to 2015
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 259952644
Treatment options for osteosarcoma patients usually include chemotherapy and surgical resection. These therapeutic strategies have a deleterious impact on the quality of life in many cases and often are not able to prevent fatal consequences. There has been little effort in osteosarcoma treatment in terms of patient survival in the last years. The main reason is the lack of new and effective agents. Many drug candidates demonstrated promising therapeutic potential in vitro and in vivo but prove to be ineffective when trialed in humans. This is due to a range of factors including variations in the behaviour of cancer cells in different microenvironments. Being a bone tumour, osteosarcoma growth is influenced by extracellular bone components and the surrounding bone marrow stem cells. The currently used in vitro and in vivo models fail to represent the complex composition of this human bone organ. Especially intratibial tumour cell injection into immunocompromised mice is widely spread accepting the limitations of human osteosarcoma growth within a murine bone environment. The main objective of the projected study is to create a new tissue engineered orthotopic-humanised in vivo osteosarcoma mouse model with a primary tumour growing at the femur surrounded by its physiologic human bone microenvironment in order to minimize interference by the host organism. Tumour biology and clinical relevant growth properties including imaging of the metastatic spread will be evaluated. Gene array analyses will depict differences in gene expression patterns between the orthotopic humanised femoral growth site and other growth sites (murine intratibial and a subcutaneous humanised heterotopic location) as well as in metastatic lesions. To validate this first orthotopic humanised osteosarcoma model as a drug-testing platform we will evaluate the influence of doxorubicin (according to the COSS and EURAMOS treatment protocol) and the new mTOR-Inhibitor PP242 (inhibiting mTOR-Complex 1&2). We aim to identify novel biomarkers for various stages of cancer, primary tumour and metastatic lesions. Such biomarkers provide valuable information for clinicians in decision making for chemotherapeutical options and surgical management. The projected study may provide one step further to patient specific osteosarcoma treatment and risk adopted therapy. Simultaneously, this new tissue engineered orthotopic-humanised model will be evaluated for its accuracy of representing the human bone organ as a toolbox for research in other scientific disciplines like haematology and osteology.
DFG Programme
Research Fellowships
International Connection
Australia
