Description
Cancer severely affects the quality of life and represents one of the major causes of death worldwide. Better understanding of general molecular mechanisms contributing to cancer development is needed for timely diagnosis and for designing novel treatment strategies. Main aim of the project is to increase our knowledge of general molecular mechanisms of cell function. In addition we will identify new pathogenic mechanisms contributing to cancer and potentially novel biomarkers and pharmacological targets. We will elucidate the role of protein phosphatases and kinases in cellular responses to DNA damage and their involvement in cancer development. Identified molecular mechanisms will be tested for the ability to regulate the sensitivity of cancer cells to established treatments such as chemotherapy and radiotherapy. By combining cutting edge molecular biology, cell biology and biochemical approaches with analysis of clinical samples we will elucidate physiological roles of DNA damage response pathway and its involvement in cancer.
Summary of project results
Cancer is a life threatening disease caused by accumulation of genetic aberrations that stimulate uncontrolled cellular proliferation and also impact on the sensitivity to treatment. PHOSCAN project significantly contributed to the understanding of general molecular mechanisms involved in control of genome integrity. In particular, we have found that protein phosphatases WIP1 and PP1 play important roles in restricting cellular response to DNA damage. In addition, PHOSCAN project helped to identify several novel aberrations in these signalling pathways present in cancer that could potentially be exploited for targeted therapy. We observed that cancer cells carrying truncated WIP1 do not adequately respond to DNA damage and therefore are more sensitive to certain forms of chemotherapy and to nutlin-3. Further we found that sensitivity of cancer cells to PARP inhibitors is influenced by phosphorylation of RAD51 and by expression level of RNF168. Finally, we found that combination of Wee1 and Chk1 inhibitors efficiently eradicates cancer cells due to triggering unscheduled replication. Data accumulated during PHOSCAN project provide theoretical background for determining sensitivity of cancer cells to chemotherapy and may be exploited for future preclinical studies. By studying general molecular mechanisms, PHOSCAN project identified several new pathways impaired in cancer cells that can contribute to cancer development and influence the sensitivity to treatment. As short-term outputs PHOSCAN project delivered 7 scientific publications. In long term, this project generated background for future research including basic research and preclinical testing. The results were also presented on numerous conferences, including a meeting focused on Cancer Genetics organised by Project Promoter. Multidisciplinary cancer research is needed to improve public health, and therefore it is believed that the socio-economic impact of the PHOSCAN project is high.
Summary of bilateral results
Donor partnership allowed exchange of the scientific expertise and of some essential reagents between the participating teams. The Partnership allowed to develop collaboration between teams that would otherwise compete in the same research field as well. Sharing reagents, access to equipment and expertise allowed us to accomplish project outcomes and outputs of the PHOSCAN project. By studying general molecular mechanisms, PHOSCAN project identified several new pathways impaired in cancer cells that can contribute to cancer development and influence the sensitivity to treatment. In long term, this project generated background for future research including basic research and preclinical testing. The results were also presented on numerous conferences, including a meeting focused on Cancer Genetics organised by Project Promoter.