EAU 2018: Targeting of BRD4 with JQ1, Combined with Mitomycin C as a Novel Combination Therapy for Non-muscle Invasive Bladder Cancer
Current treatment options for NMIBC are intravesical mitomycin-C [MMC] (typically for lower risk disease) or intravesical BCG (for high-risk disease or CIS). In conjunction with a relatively high recurrence and progression rate for NMIBC, despite these therapies, the global supply chain shortages of BCG have further limited our ability to conservatively manage NMIBC. It further demonstrated the dire need for additional therapies in this disease space.
In this study, the authors took a more shotgun approach to identifying novel therapeutic agents. In collaboration with the Structural Genomics Consortium (Oxford, UK), they screened a panel of epigenetic modulators for their ability to synergise with MMC against bladder cancer cell lines. In doing so, they identified JQ1, an inhibitor of BRD4. However, mere identification is insufficient – establishing efficacy and safety is critical.
In this early publication of data, they note that JQ1 alone was able to reduce the viability of bladder cancer cell lines in a dose-dependent fashion (T24 cell line). In additional, JQ1 given in combination with MMC increased the efficacy of the MMC, further reducing cell viability. They were synergistic.
Further in-vitro experiments demonstrated that a 1 hour pulse treatment, mirroring a 1 hour intravesical exposure, either together or staggered, of MMC and JQ1 was sufficient to induce significant cell death. MMC +/- JQ1 caused cells to arrest in the S/G2 cell cycle phase with induction of significant DNA double-strand breaks, whereas JQ1 alone caused cell cycle arrest at the G1 phase. Apoptosis was at least partially responsible for the cell death observed. JQ1 also reduced cell migration in scratch-wound assays. Finally, as expected of a BRD4 inhibitor, JQ1 was able to modulate the protein expression of BRD4 downstream targets including C-MYC and this activity was not modulated by MMC.
However, they stopped short with in vitro analyses, and further orthotopic models are needed to establish efficacy in a bladder model. In vitro pulse doses only loosely model intravesical exposure.
The results are promising, and require further preclinical assessment.
Speaker: C. Simm
Co-Authors: Caridis A., Di Maio A., Knowles P., Gorman B., Jones R., Ward D., Oppermann U., Bountra C., Khanim F., Bryan R.
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd, at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark