Modulation of the TRAIL apoptotic pathway to optimize chemoradiation in preclinical models of cervical cancer

PhD ceremony: Ms. S. Tan, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Modulation of the TRAIL apoptotic pathway to optimize chemoradiation in preclinical models of cervical cancer

Promotor(s): prof. S. de Jong, prof. E.G.E. de Vries, prof. A.G.J. van der Zee

Faculty: Medical Sciences

Cervical cancer is the 5^th most common cancer in women worldwide . Locally advanced disease is treated with chemoradiation. This treatment results in 66-79% 5-year survival. Further escalation of chemoradiation doses to increase treatment efficacy is limited by the small therapeutic window. Novel targeted agents with often a different toxicity profile are therefore considered to be of potential interest to be tested.

This thesis focuses on exploring the potential of death receptor 4 (DR4) or 5 (DR5) targeting ligands such as tumour necrosis factor-related apoptosis inducing ligand (TRAIL) in combination with anticancer agents to enhance treatment efficacy. First, an overview of potential new drugs to be combined with chemoradiation in human papilloma virus (HPV) positive cervical cancer is presented. The role of high risk HPV16 E6 has been investigated by selective silencing of E6 RNA. Next, in preclinical models the distinct apoptotic pathways activated by the proteasome inhibitor bortezomib in combination with agonistic DR4/DR5 monoclonal antibodies have been solved. Recombinant human (rh)TRAIL, the DR5-selective rhTRAIL and the agonistic DR4 antibody mapatumumab were combined with irradiation to improve radiotherapy efficacy in vitro and in mice bearing a bioluminescent human cervical cancer xenograft model. These results suggest that for tumours sensitive to DR4-mediated apoptosis mapatumumab, and for tumours sensitive for DR5-mediated apoptosis DR5-selective TRAIL is more effective than wild-type rhTRAIL. The results support further exploration of chemoradiation treatment combined with mapatumumab in cervical cancer patients.