Targeting apoptosis in cancer cells: improving TRAIL death receptor signaling

PhD ceremony: Ms. A. Meijer, 14.30 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Targeting apoptosis in cancer cells: improving TRAIL death receptor signaling

Promotor(s): prof. S. de Jong, prof. E.G.E. de Vries, prof. F.A.E. Kruyt

Faculty: Medical Sciences

This thesis deals with apoptosis, a regulated form of cell death. Deregulation of apoptosis is one of the causes of cancer. Therefore, specific reactivation of apoptosis is potentially of interest for cancer treatment. Apoptosis can be induced with a TNF family member, i.e., rhTRAIL. Interestingly, it induces apoptosis in cancer cells, without harming normal cells. However, recent clinical data revealed that the efficacy of rhTRAIL needs to be improved. The aim of this thesis was to optimise rhTRAIL-induced apoptosis. In preclinical models we showed that various new combination therapies with rhTRAIL strongly enhanced apoptosis, for example in ovarian cancer cells. The combination of chemotherapy with rhTRAIL induced high apoptosis levels in cancer cells that were resistant to single treatment. In addition, the combination of rhTRAIL with inhibition of the so called insulin receptor resulted in strong apoptosis in both ovarian- and lung cancer cells. The application of modified rhTRAIL variants improved the observed effect. Finally, a new model was investigated in which tumor slices of fresh human ovarian cancer tissue were generated. This model allowed individual treatment of these slices with various combination therapies. We demonstrated that the combination of the new drug nutlin-3, chemotherapy, and rhTRAIL, massively induced apoptosis in these cultured slices of human cancer tissue. Further studies are required to investigate whether these new combination strategies with rhTRAIL are applicable for clinical use.