We are investigating DNA damage signalling and repair factors in bladder cancer to develop new radiotherapy-based treatments and to identify markers to select the most suitable treatments for individual patients.
Patients with muscle-invasive bladder cancer (MIBC) can be treated by radiotherapy rather than having their bladder surgically removed. Adding chemotherapy to radiotherapy makes the tumour more sensitive to radiation and improves outcomes at the expense of toxicity to surrounding normal tissues. We are trying to find effective drugs which have minimal effects, and the histone deacetylase inhibitor panobinostat is showing promise in this regard. We are elucidating the mechanisms underlying its radiosensitising properties, which should allow the development of more specific agents, thus reducing overall drug toxicity. Panobinostat downregulates the MRE11-RAD50-NBS1 complex post-transcriptionally, and we are using mass spectrometry (collaboration with Prof Benedikt Kessler) to study acetylation sites and dynamics in non-histone HDAC inhibitor protein targets involved in DNA repair pathways, which may be exploitable therapeutically (Figure 1). As chromatin regulation appears to be a major drive mechanism/hallmark of bladder cancer, we are also investigating bromodomain inhibitors as radiosensitisers. In another approach, we are looking to target agents directly to the bladder, through microbubble formulations (in collaboration with Profs Eleanor Stride and Boris Vojnovic) where drugs can be released locally by focused ultrasound (Figure 2).
We are also looking for markers in patients' tumours to help patients choose between radiotherapy and surgery in MIBC. One such marker is the DNA damage signalling protein MRE11, which we found predicted patient survival after radiotherapy but not surgery, and this result was validated independently. Muscle-invasive bladder tumours have a truncated version of MRE11 which we hypothesise is acting in a dominant-negative manner and work is underway to investigate this. We are now seeking to exploit the TCGA and other data in MIBC to develop a gene signature and immunohistochemistry panel of biomarkers predictive of radiotherapy outcome. We have been involved in an exciting Citizen Science project, Reverse the Odds, where members of the public score our tumour samples, based on pattern recognition.