(170f) Combinatorial Treatment Using Lipopolymer-Mediated TRAIL Gene Delivery and Kinase Inhibitors for Bladder Cancer

The estimated number of new cancer cases within the US for 2016 is 1,658,270 with 595,690 deaths projected during the same year. Urinary bladder cancer is the 6^th most common type of cancer in men with 77,000 new cases and 16,400 deaths expected for both men and women in 2016. Treatments for bladder cancer depend on the type and stage of cancer and may involve surgical removal of the tumor, immunotherapy, chemotherapy (intravenous or intravesical), radiation, and/or surgery for bladder removal. Limitations of current chemotherapy regimens include poor drug bioavailability, drug resistance and toxicity, and additional side-effects on healthy cells. Therapies that can specifically target tumor cells can improve patient treatment and quality of life. Tumor Necrosis Factor-alpha Related Apoptosis-Inducing Ligand (TRAIL) induces programed cell death in several cancer types with minimal effect on normal cells, making it a desirable target for cancer treatment. However, resistance to TRAIL (either intrinsic or acquired) has been observed in cancers possibly due to overexpression of anti-apoptotic proteins or low expression of TRAIL receptors. Combination therapy using TRAIL may be a key strategy to sensitize cancer cells to TRAIL-induced apoptosis.

The current work investigates the treatment efficacy of using kinase inhibitors in combination with TRAIL gene delivery in bladder cancer cells. Protein kinases are involved in metabolism, transcription, cell cycle progression, and apoptosis and are linked to TRAIL resistance. The two kinase inhibitors chosen, TG101209 (a Janus kinase II inhibitor) and HMN-214 (a polo-like kinase inhibitor), were based on a previous kinase screen that showed enhanced transgene expression using these inhibitors. Novel aminoglycoside-derived lipopolymers were used for the delivery of a plasmid expressing TRAIL (pEF-TRAIL) in UMUC3 bladder cancer cells. These aminoglycoside-derived lipopolymers displayed enhanced transgene expression compared to parental polymers as well as PEI. A dose-response study suggested that the combined treatment of pEF-TRAIL and TG101209 or HMN-214 demonstrated significantly enhanced cell death compared to either treatment alone. In vivo studies confirmed a significant decrease in tumor volume in mice treated with the TRAIL plasmid alone. Experiments with the combination treatments in vivo are currently underway. This study demonstrates the effectiveness of aminoglycoside-derived lipopolymers for combinatorial treatments using pEF-TRAIL and kinase inhibitors, and suggests potential applications of this treatment in the clinic.