The Histone Deacetylase Inhibitor Romidepsin Spares Normal Tissues While Acting as an Effective Radiosensitizer in Bladder Tumors in Vivo

Muscle-invasive bladder cancer has a 40-60% five-year survival rate with radical treatment by surgical removal of the bladder or radiotherapy-based bladder preservation techniques, including concurrent chemoradiation. Elderly patients cannot tolerate current chemoradiotherapy regimens and so often only receive radiotherapy which is less effective. We urgently need to find effective chemotherapy agents for use with radiotherapy combinations which are non-toxic to normal tissues and tolerated by elderly patients. We have identified HDACi as promising agents to study. Pan-HDAC inhibition, using panobinostat, is a good strategy for radiosensitisation, but more selective agents may be more useful radiosensitisers in a clinical setting, resulting in fewer systemic side effects. Here, we study the HDAC class I-selective agent romidepsin, which we predict to have fewer off-target effects than panobinostat, while maintaining an effective level of tumour radiosensitisation. In vitro effects of romidepsin were assessed by clonogenic assay and showed that romidepsin was effective in the nanomolar range in different bladder cancer cells and radiosensitised these cells. The radiosensitising effect of romidepsin was confirmed in vivo using superficial xenografts. The drug/irradiation combination treatment resulted in significant tumour growth delay but did not increase the severity of acute (3.75 days) intestinal normal tissue toxicity nor late toxicity at 29 weeks. Moreover, we showed that romidepsin treatment impaired both HR and NHEJ DNA repair pathways, suggesting that the disruption of the DNA repair pathways caused by romidepsin is a key mechanism for its radiosensitisating effect in bladder cancer cells. The results of this study demonstrate that romidepsin is an effective radiosensitiser in vitro and in vivo and does not increase the acute and late toxicity after ionising radiation. As romidepsin is already in clinical use for the cutaneous T-cell lymphoma, a phase I clinical trial of romidepsin as a radiosensitiser could be considered in muscle-invasive bladder cancer.