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

Abstract

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 HIF-1A 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)

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

“…7 Similarly, it has been previously reported that hypoxia and HIF-1a lead to the development of osteolytic lesions and tumor growth in breast cancer in vivo models. 26 In conclusion, as in other tumoral models where it has been shown that HIF-1a inhibition exerts a potent in vivo antitumor effect, including the squamous cell carcinoma, liver and lung cancer, 48,49 our data indicate that selective HIF-1a inhibition results in a potent anti-MM effect by blocking angiogenesis and the development of osteolytic bone lesions. These results suggest that HIF-1a is a potential therapeutic target in MM.…”

Targeted Knockdown of SEPT9_v1 Inhibits Tumor Growth and Angiogenesis of Human Prostate Cancer Cells Concomitant with Disruption of Hypoxia-Inducible Factor-1 Pathway

“…The pharmacologic validation of HIF-1 as a therapeutic target has not been fully elucidated because of the lack of selective inhibitors (6). The potential outcome of HIF-1 inhibition in cancer therapy is promising, based on genetic approaches and preclinical models (1,6), and the shRNA targeting of HIF-1α was shown to inhibit tumor growth (33,34). In this study, we provide further evidence that disruption of the HIF-1 pathway by targeting its upstream activator SEPT9_i1 with shRNA is effective for tumor growth inhibition.…”

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

“…However, the roles HIF-1a plays in hypoxiarelated drug resistance are still inconclusive. 6,10,[30][31][32][33] Moreover, how HIF-1 cooperates with p53 to determine drug sensitivity remains poorly known. Inhibition of glucose transport-1 expression and also drug resistancerelated proteins such as mdr1, mrp and lrp, and increased level of proapoptotic proteins such as Bid and Bax were ever reported to form the therapeutic basis of HIF-1 interference.…”