Funding tool: Basic research projects
Project-ID: LS11-002
Project start: 01. September 2012
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 279.000,00

Brief summary:

Aim of this project is to study the role of hypoxia in chemotherapy. This will be achieved by close cooperation between the IMC in Krems, the University of Vienna and the Molecular Imaging group at the AIT Austrian Institute of Technology. Hypoxia in tumors is often regarded as a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, invasiveness and metastasis, resistance to cell death, altered metabolism and genomic instability. Hypoxia in tumors arises because of oxygen diffusion limitations in prominent avascular areas. The diffusion-limited hypoxic conditions cannot be mimicked in conventional 2D monolayer cell cultures. Likewise the 2D cell models cannot integrate the complex cellular microenvironment of the tumor that often plays a critical role in determining the physiological consequences of hypoxia in carcinomas. Due to the limitations of conventional 2D cell cultures we will primarily employ 3D organotypic cancer models to explore the various molecular and physiological consequences of hypoxia in human cancer. The proposed 3D tumor models will exhibit varying levels of complexities and will consist of either i) human tumor cell lines derived from breast, lung and colon carcinomas, ii) co-cultures of tumor cell lines and various types of tumor-associated stroma cells, or iii) primary tumor and stroma cells derived from human cancer tissue. The cancer cell lines will be selected according to their applicability in large-sized 3D cultures and their genetic and biochemical alterations that are functionally associated with hypoxia (e.g. receptor tyrosine kinase signaling, PTEN, HIF1/HIF2, the unfolded protein response (UPR), signaling and glucose metabolism). From these results, 2 different tumor types will be identified for the generation of xenograft models. These xenografts will undergo in vivo FDG-PET (to determine glucose consumption) and hypoxia PET scans on consecutive days. From the in vivo PET data pharmacokinetic modeling will be performed, to identify the parameters whichdisplay the strongest correlation with the late time hypoxia tracer retention (hypoxia). Finally, the characterized 2D and 3D cell cultures that show a high degree of hypoxia as well as the in vivo models will be treated with an anticancer agents, and the therapy response will be monitored. Here the comparison between the in vitro and in vivo results will be of high interest as it is not yet known in how far the 3D cell cultures reflect the in vivo tumor environment especially when exposed to anticancer drugs.

Keywords:
Hypoxia, PET, 3D tumor cell cultures