Gene amplification is an important mechanism in cancer cells to overexpress cancer-promoting driver genes. Especially, high-level amplifications have a clear impact on gene expression and these alterations are often associated with poor prognosis. A gene named PPFIA1, which encodes for liprin-α1, is one of the most frequently amplified genes in squamous cell carcinoma of head and neck (HNSCC). It is located at the 11q13 region, which is commonly amplified in multiple cancers in addition to HNSCC. 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 (Pehkonen et al., 2016). 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 (Pehkonen et al., 2018). As liprin-α1 has significant contribution in oncogenic signalling (Pehkonen et al., 2021), our goal is to investigate its role as a drug response biomarker. These studies will enable us to investigate the mechanisms behind liprin-α1 in oncogenic phenotype and tumor progression.
Our research on rare cancers is part of the Finnish iCAN Digital Precision Cancer Medicine Flagship (www.ican.fi) that enables the integration of molecular profiling information from tumors with rich longitudinal health care provider data. Rare tumors often lack proper pre-clinical models, their diagnostics may be challenging, and clinical trials are limited due to low numbers of cases. There is a need to harmonize the treatment, and, on the other hand, personalize the treatment. The purpose of the iCAN-RARE research project is to systematically profile rare human tumor types and to compare the obtained molecular information with those of the other tumor types, which may reveal biological targets for novel treatments. We prospectively collect tumor tissue from rare cancers including gastrointestinal stromal tumor (GIST) and other soft tissue sarcomas, salivary gland tumors, rare gynecological tumors, and neuroendocrine tumors. These tumors are subjected to molecular profiling such as RNA and exome sequencing and immune profiling. Primary tumor cultures (2D cell cultures, spheroids) are used for the assessment of therapeutic responses in high content molecular library screening using multiplex fluorescence imaging. Selected therapeutic agents are validated in 3D ex vivo cultures. These data are linked with patient hospital records and Finnish health registry data to further evaluate the novel disease targets. The goal of this project is to systematically characterize rare tumors and explore targeted treatment options for rare cancers.
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 carried out a drug screening for genetically and clinically well-characterized head and neck squamous cell carcinoma UT-SCC cell lines because testing large amount of drugs and their combinations in clinical trials is challenging (Lepikhova, Karhemo et al., 2018). 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.