Evaluating hypoxia-inducible factor-1alpha 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 hypoxia-inducible factor-1alpha (HIF-1alpha) in established tumors. We showed that HIF-1alpha inhibition resulted in transient tumor stasis or tumor regression, and inhibiting HIF-1alpha in early-stage tumors was found to be more efficacious than inhibiting HIF-1alpha in more established tumors. A differential requirement of HIF-1alpha for tumor growth was also observed among different tumor types. Examination of tumors resistant to HIF-1alpha inhibition suggested that the resistance might result from a less hypoxic tumor environment and the level of HIF-1alpha 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.
Li
Leiming
L
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Lin
Xiaoyu
X
Staver
Michael
M
Shoemaker
Alexander
A
Semizarov
Dimitri
D
Fesik
Stephen W
SW
Shen
Yu
Y
D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D014157:Transcription Factors; D004318:Doxycycline