More recently, we have also expanded our studies to rare tumors. Due to the low frequencies, pre-clinical models and research are often limited. Thus, molecular profiling and ex vivo drug testing may provide important information in clinical diagnostics and novel treatment options for rare tumors. Below, you can find more information about our ongoing projects.
Gene amplification in cancer cells provides a means for overexpression of cancer-promoting driver genes. Especially, high-level amplifications have a clear impact on gene expression and these alterations are often associated with poor prognosis. We are interested in 11q13 amplification, which is one of the most commonly amplified regions in several epithelial cancers. We are studying the oncogenic role of two genes, PPFIA1 and ANO1, encoding liprin-α1 and anoctamin 1, and how they contribute to cancer progression, cell adhesion and invasion in squamous cell carcinoma of head and neck (HNSCC) and breast carcinoma cell lines. For example, liprin-α1 is an essential protein in regulating focal adhesion dynamics, cell spreading and organization of cytoskeleton. We have found that liprin-α1 is a novel regulator of the tumor cell intermediate filament vimentin with differential oncogenic properties in actively proliferating or motile cells. Furthermore, liprin-α1 knockdown leads to the upregulation of transmembrane protein CD82, which is a suppressor of metastasis in several solid tumors, linking liprin-α1 to the cancer cell invasion and metastasis pathways. Our main goal in these projects is to understand the molecular mechanisms by which genes activated by gene amplification contribute to oncogenic signalling and tumor progression.
Understanding the underlying genetic alterations in a tumor has provided novel opportunities for cancer treatment. Gastrointestinal stromal tumor (GIST) is one example in which patients with activating mutation in receptor tyrosine kinase KIT can be treated by small molecule inhibitor imatinib. GIST is a rare tumor occurring mostly in the stomach or small intestine. The imatinib therapy has revolutionized the treatment of GIST and has significantly improved survival of the patients. Despite the survival benefit, the emergence of drug resistance is a challenge. Understanding the determinants of drug response and the mechanisms that make these tumors resistant for the treatment are essential. Lack of representative pre-clinical models has been a challenge in testing novel therapeutics in GIST. Thus, we are using e.g. patient-derived ex vivo models and next-generation sequencing to characterize the tumors and to identify molecular mechanisms that relate to drug resistance for current inhibitors.
We have also carried out a drug screening for genetically and clinically well-characterized head and neck squamous cell carcinoma (HNSCC) cell lines because testing large amount of drugs and their combinations in clinical trials is challenging. Opposite to GIST, HNSCC has no clinically approved biomarkers for therapy response for targeted agents. The only approved targeted agents for advanced HNSCC are cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), and the immune checkpoint inhibitors nivolumab and pembrolizumab. In particular, patients with inoperable recurrent head and neck carcinomas pose a difficult therapeutic challenge. We have identified several genetic alterations that associate to drug responses of mTOR, MEK, and EGFR inhibitors, currently in clinical use for multiple cancers. In addition, we are exploring factors that associate to drug response of boron neutron capture therapy (BNCT), which is a promising biologically targeted radiotherapy for the treatment of HNSCC. Finding novel drug response biomarkers and mechanisms of drug resistance may provide significant benefits in targeted therapeutics of cancer.
We are utilizing novel pre-clinical ex vivo tumor models for drug testing, biomarker validation and molecular studies. In humans, tumors grow in a three dimensional (3D) environment in which their behavior is controlled through interactions with other cells and extracellular matrix. Therefore, we use patient-derived primary biopsy samples and different matrices to grow explants, in vitro 3D cellular clusters derived from the primary tissue. Our ex vivo cultures represent the cell types in the original tumor and thus are optimal preclinical models for drug testing.