Targeting the extrinsic apoptosis pathway in ovarian cancer

Ovarian cancer is among the most lethal of all malignancies in women. In The Netherlands its incidence is about 10 times lower than for breast cancer, whereas its mortality rate is three times higher (1). The main cause of this high lethality is the advanced stage of disease present in the majority of patients at the time of initial diagnosis. As the disease is generally asymptomatic early in its progression and the molecular pathogenesis is poorly understood, strategies for early detection and prevention have not yet been successful. Treatment of advanced stage ovarian cancer, consisting of combined modality treatment with surgery and chemotherapy, yields initial response rates of over 80%, with 40-60% complete responses (2). However, the vast majority of patients dies within five years after disease manifestation with drug-resistant cancers. The possibility to escape apoptosis is defined as one of the hallmarks of carcinogenesis (3) and is a major factor involved in chemotherapy resistance (4). Apoptosis results from caspase activation brought upon through two separate pathways. Since the intrinsic pathway is commonly disrupted in cancer cells, targeting the extrinsic pathway by ligand-activation of cell-surface death receptors is regarded as a promising strategy to overcome apoptosis resistance. The recombinant human form of the TNF-family member TRAIL and other drugs directed at its agonistic receptors DR4 or DR5 induce apoptosis in a wide variety of human cancer cell lines and their xenografts, including ovarian carcinoma cells, without being toxic to normal tissues. Furthermore, combination of these agents with conventional chemotherapeutics and radiotherapy results in enhanced cytotoxicity. RhTRAIL and monoclonal antibodies targeting DR4 or DR5 are currently evaluated in early phase clinical studies. The aim of this thesis was to explore the potential of rhTRAIL and DR4 or DR5targeting drugs as anticancer agents, with the focus on ovarian cancer