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 5th 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.
Last modified: | 13 March 2020 01.02 a.m. |
More news
-
06 June 2025
India-Netherlands Hydrogen Valley Fellowship Programme announced
To coincide with World Environment Day, 5 June 2025, the Indian Department of Science and Technology and the University of Groningen yesterday announced a Hydrogen Valley Fellowship Programme Partnership, allowing talented Indian scholars working on...
-
28 May 2025
Gaan avondmensen cognitief sneller achteruit dan ochtendmensen?
Wie ’s avonds opleeft en laat naar bed gaat, heeft een grotere kans op cognitieve achteruitgang dan een ochtendmens, blijkt uit UMCG-onderzoek.
-
27 May 2025
An adventure in the brain
In the exhibition Brainstorm in the University Mueseum, Iris Sommer and two other brain researchers from Groningen explain the gut-brain connection, how it was discovered that the brain does what it does, and how games motivate you to perform...