The anthracycline drug doxorubicin, is one of the most used chemotherapeutic drugs, with over one million patients treated every year. However, the exact molecular mechanism by which this drug kill... Show moreThe anthracycline drug doxorubicin, is one of the most used chemotherapeutic drugs, with over one million patients treated every year. However, the exact molecular mechanism by which this drug kill tumor cells remain unclear. In addition, treatment with anthracyclines coincides with severe adverse effects such as cardiotoxicity, secondary tumor formation and gonadotoxicity. Understanding how these highly effective anticancer drugs function and why they cause these severe toxicities would have tremendous impact on cancer treatment and the quality of life of cancer survivors. Therefore, even today, studying old anticancer drugs has high therapeutic potential and opens new exciting paths to improve currently available treatment options. Show less
The aim of my work was to identify novel proteins that are involved in different aspects of disease biology, in the hope that we can target these to treat the disease. Using large-scale screening... Show moreThe aim of my work was to identify novel proteins that are involved in different aspects of disease biology, in the hope that we can target these to treat the disease. Using large-scale screening technologies, I found a novel regulator of chemosensitivity to the anti-cancer drugs etoposide and doxorubicin. Furthermore, novel proteins and drugs that target MHCII antigen presentation were picked up. Interestingly, one of these drugs is currently used in the clinic to treat MHCII-dependent autoimmune diseases, but for which the mechanism of action is unknown. Lastly, these screens yielded enzymes that control the dynamics of endosomes in the cell, which can potentially be targeted in cancers that rely on overactivation of growth signaling receptors. Taken together, my work has provided new potential targets for the treatment or classification of several tumor types, as well as a potential mechanism of action for a widely used drug. Show less
Osteosarcoma is the most frequent malignant bone tumor affecting mainly adolescents and people older than 50years old. Current treatment involves chemotherapy and surgical removal. Despite efforts... Show moreOsteosarcoma is the most frequent malignant bone tumor affecting mainly adolescents and people older than 50years old. Current treatment involves chemotherapy and surgical removal. Despite efforts to find a cure, there is 70% 5year survival rate. For patients that present metastasis at the moment of diagnosis, the prognosis is worse. Additionally, many do not respond well to chemotherapy. The aim of this research was to find new treatment options for patients with osteosarcoma. I searched for inhibitors that could sensitize osteosarcoma cells to chemotherapy. In this thesis, it is shown that targeting cell cycle regulators, proteins involved in apoptosis inhibition, and cellular pathways involved in survival, proliferation and migration are promising candidates for further research. Show less
Immunotherapy and chemotherapy are major strategies in current cancer treatments. In the first half of this thesis, a new way of antigen cross-presentation from apoptotic cells to APCs, mediated by... Show moreImmunotherapy and chemotherapy are major strategies in current cancer treatments. In the first half of this thesis, a new way of antigen cross-presentation from apoptotic cells to APCs, mediated by gap junctions, is described. And potential anti-tumor applications of gap junction mediated antigen cross-presentation are discussed in the context of the current knowledge. In the second half of this thesis, an unexpected novel mechanism of action__selective induction of histone eviction__is described, which could explain the long standing clinical observation that anthracycline members, like doxorubicin, daunorubicin and aclarubicin, are efficient but with long term side-effects such as cardiotoxicity Show less
In order to form a distant metastasis, a cancer cell has to migrate out of the primary tumor, intravasate into a blood or a lymphatic vessel, subsequently survive in the absence of cell-cell and... Show moreIn order to form a distant metastasis, a cancer cell has to migrate out of the primary tumor, intravasate into a blood or a lymphatic vessel, subsequently survive in the absence of cell-cell and cell-matrix interactions, extravasate the blood or lymphatic vessel, migrate through the target organ and finally proliferate to grow out into a full metastasis. During all of these processes, specific kinases are involved in the concerted activation of distinct signaling pathways. We hypothesised that the protein tyrosine kinase FAK plays a crucial role in one or multiple of the processes involved in the formation of metastases. Therefore, the overall aim of the studies described in this thesis was to investigate the role of the non-receptor protein tyrosine kinase FAK in the distinct processes involved in tumorigenesis and metastasis and to unravel the involved downstream signaling pathways. Moreover, the potential of a combined therapy of the inhibition of FAK and exposure to the cytostatic doxorubicin was tested, as well as dissection of the intracellular events downstream of FAK. Show less
