Our previous work has shown that knock-down of a critical IAP molecule using RNA interference techniques is capable of overcoming a barrier to cancer cell death in a previously significantly apoptosis-resistant human lung cancer cell line. Since the last reporting, we have performed preclinical work investigating three members of a novel drug class which inhibits the same IAP molecule pharmacologically and determine its efficacy in lung cancer cells. Our results appeared to show that all members tested from this new pharmacologic drug class are as effective as RNA interference techniques. However, in a small minority of lung cancer cells the drug was ineffective in diminishing the IAP's effects to prevent cancer cell death. In contrast, in the majority of lung cancer cells, these small molecule drugs can exert similar effects of rendering cell-death (apoptosis) resistant cells neo-susceptibility to apoptosis induction. Our current work is focused on completing the necessary preclinical work to translate this drug class into the clinical setting and delineating the mechanism(s) for drug resistance of this small molecule mimic in lung cancer, as this would hold direct implications as to the appropriate patients who should and should not receive this drug in a clinical trial. In this first goal, we are taking three approaches: 1) to bring this new drug class directly into clinical trials upon completion of preclinical studies, provided the availability of the drug for use in the NIH Clinical Center;2) to investigate the effectiveness of creating a targeted nanoparticle delivery of our (already effective in-vitro) RNAi modulation of the apoptosis pathway;and 3) to develop a targeted delivery approach of pro-apoptosis payload using a virus-like particle (VLP) construct. In approach #1, we are currently completing in-vitro experiments to confirm the activity of a model drug prior to the in-vivo evaluation in small animal models using the novel combination of this small molecule mimic and an upstream apoptosis inducer. In approach #3, we have begun some preliminary work using a TRAIL-targeted VLP and is currently working with our collaborators to re-design the targeting ligand to better effect stimulation of the apoptosis pathway upon VLP docking with the lung cancer cell. Lastly, we are just beginning experimental work in approach #2.
| Tobin, Lisa A; Xie, Yili; Tsokos, Maria et al. (2013) Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo. Biomaterials 34:2980-90 |
