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 begun to explore a novel drug which inhibits the same IAP molecule pharmacologically and determine its efficacy in lung cancer cells. Early results appeared to show that the pharmacologic drug is as effective as RNA interference techniques but in a minority of lung cancer cells the drug was ineffective in diminishing the IAP's effects to prevent cancer cell death. However, in the majority of lung cancer cells, this small molecule can exert similar effects of rendering cell-death (apoptosis) resistant cells neo-susceptibility to apoptosis induction. Our current work is focused on delineation of 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. Next, we will perform proof-of-principle in vivo evaluation in small animal models using the novel combination of this small molecule mimic and an upstream apoptosis inducer. A potential barrier has been the acquisition of enough of the small molecule mimic in order to proceed with such studies. As such, we are actively negotiating with several pharmaceutical sources in order to obtain the drug. However, we may alternatively need to contract synthesis of the molecule for further scientific work if extramural pharma cannot be obtained from extramural sources.
| 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 |
