DNA damage responses in tissues and tumours

We study DNA damage responses in cells within tissues and tumours. In collaboration with the Departments of Internal Oncology and Pathology we develop novel techniques to study DNA repair, cell cycle checkpoint activation and apoptosis in living breast and ovarian tumour slices, with the ultimate goal to develop methods to predict treatment response in the tumour. The primary focus is at this moment on tumour sensitivity to PARP inhibitors, which are in clinical trials for hereditary breast and ovarian cancer, but may also be useful for treatment of selected sporadic tumours. In addition to germline mutated BRCA2-deficient tumors, we also identified BRCA1 promoter methylation and other defects that can inhibit homologous recombination repair of DNA double strand breaks, making them PARP inhibitor sensitive.

Tissue tumor

In collaboration with the Departments of Urology and Pathology, we developed similar DNA damage response assays for bladder and prostate cancer. Again, the primary goal is to predict therapy response. We showed that expression levels of the Nucleotide Excision Repair (NER) protein XPC cannot be used to predict NER capacity of bladder tumors.
In collaboration with Prof. Casper van Eijck we are currently also adapting this technology to study gastrointestinal tumors, including neuroendocrine pancreas tumors.

Publications

Naipal, K.A.T.,  Verkaik, N.S., Ameziane, N., van Deurzen, C.H.M., ter Brugge, P., Meijers, M., Sieuwerts, A.M., Martens, J.W., O’Connor, M.J., Vrieling, H., Hoeijmakers, J.H.J., Jonkers, J., Kanaar, R., de Winter, J.P., Vreeswijk, M.P., Jager, A., van Gent, D.C. (2014) Functional ex vivo assay to select Homologous Recombination deficient breast tumors for PARP inhibitor treatment. Clin. Cancer Res. 20,4816-26.


Naipal, K.A.T., Raams, A., Bruens, S.T., Brandsma, I., Verkaik, N.S., Jaspers, N.G.J., Hoeijmakers, J.H.J., van Leenders, G.J., Pothof, J., Kanaar, R., Boormans, J. and van Gent, D.C. (2015) Attenuated XPC Expression Is Not Associated with Impaired DNA Repair in Bladder Cancer. PLoS One 10, e0126029.