Abstract C038: Targeting aberrant pathways by an advanced combination regimen to effectively and safely control urothelial carcinoma

Despite treatment, >50% of urothelial carcinomas (UCs) recur and progress to life-threatening, advanced UCs. The double combination gemcitabine+cisplatin (Gem+Cis) regimen is a standard treatment for advanced UCs. Gem is a DNA synthesis-inhibiting agent, and Cis is a platinum-based, DNA-damaging agent. However, despite the initial high response rates with Gem+Cis, the overall 5-year survival rate of advanced UC patients is less than 35% largely due to drug resistance and cancer recurrence. Thus, there is a critical need to identify advanced therapeutic regimens to effectively control advanced UCs. More than 80% of UCs are associated with the aberrant induction of receptor tyrosine kinases (RTKs) to Ras to the ERK pathway. Advanced UCs are frequently accompanied with the aberrant elevation of reactive oxygen species (ROS). To efficiently pursue effective regimens, we studied combinations of FDA-approved agents to synergistically induce and reduce cancer cell death and drug resistance, respectively. Our in vitro studies detected that the integration of the histone deacetylase inhibitor romidepsin (Rom) into the Gem+Cis regimen (Gem+Rom+Cis) resulted in synergistically inducing death and suppressing drug resistance of UC cells. Instead of inhibition, Gem+Rom+Cis enhanced the aberrant RTK-Ras-ERK pathway and ROS in UC cells, along with DNA synthesis inhibition and DNA damage, to induce caspase activation and PARP proteolysis, causing cell death. In addition, our studies revealed that Gem+Rom+Cis was able to enhance the binding immunoglobulin protein (BiP). BiP, the key modulator for the unfolded protein response (UPR), is known to support tumorigenesis, cytoprotection, and drug resistance. Interestingly, our studies indicated a novel role of elevated BiP in supporting cell death but not cytoprotection. Our in vivo studies identified a tolerable protocol for administering combination regimens into animals. We also determined that the triple combination Gem+Rom+Cis regimen was efficacious in controlling UC xenografts in immune-deficient mice. The current therapeutic mainstream emphasizes the inhibition of aberrant pathways in order to regain control of cancer cell growth; however, preclinical and clinical studies have shown that inhibiting one pathway may result in the compensatory activation of other pathways to rescue cancer cells, leading to drug resistance and cancer recurrence. In contrast, our novel results indicated that Gem+Rom+Cis was able to enhance the aberrant Ras-ERK pathway, ROS, and BiP, leading to enhanced cell death and reduced drug resistance in UC cells. In conclusion, our studies identified a safe triple combination Gem+Rom+Cis regimen, effectively modulating UC-associated aberrant pathways and controlling UC tumor development in animals. The triple combination Gem+Rom+Cis regimen should be promptly considered as an advanced treatment over the conventional double combination Gem+Cis regimen in clinical trials in order to control advanced UCs, reduce mortality, and improve UC patients’ quality of life. Citation Format: Hwa-Chain Wang, Pawat Pattarawat, Shelby Wallace, Robert Donnell. Targeting aberrant pathways by an advanced combination regimen to effectively and safely control urothelial carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C038. doi:10.1158/1535-7163.TARG-19-C038