Evaluating Hypoxia-Inducible Factor-1A as a Cancer Therapeutic Target via Inducible RNA Interference In vivo

Validating potential targets is an important step in the drug discovery process. In this study, we tested the feasibility of using inducible RNA interference (RNAi) in vivo to obtain an unbiased evaluation on the efficacy of inhibiting hypoxiainducible factor-1A (HIF-1A) in established tumors. We showed that HIF-1A inhibition resulted in transient tumor stasis or tumor regression, and inhibiting HIF-1A in earlystage tumors was found to be more efficacious than inhibiting HIF-1A in more established tumors. A differential requirement of HIF-1A for tumor growth was also observed among different tumor types. Examination of tumors resistant to HIF1A inhibition suggested that the resistance might result from a less hypoxic tumor environment and the level of HIF-1A expression in tumors may be a useful marker for predicting tumor response to HIF-1 inhibition. This study shows that inducible RNAi is a versatile tool for evaluating cancer targets in vivo . In addition to broad implications on in vivo validation of cancer targets, results from this study will also be instructive for practical applications of HIF-1–based cancer therapeutics. (Cancer Res 2005; 65(16): 7249-58)