A New Inducible RNAi Model for Cancer Target Validation In Vivo
© The Author(s) 2005
Published: 8 December 2005
Human xenograft tumor models are widely used for evaluation of potential cancer targets, by assessing the anti-tumor effects of specific agents, such as siRNA. siRNA is usually stably introduced into tumor cells prior to transplantation. However, oncogene silencing results in reduced cell growth/survival in vitro and/or failure to establish tumors in vivo, thus hindering tumor response-based efficacy evaluation that is more clinically relevant. We therefore explored a new tumor response model based on regulated RNAi.
A unique RNAi vector was generated to express shRNA only after induction with doxycylcine. Using this vector, we created a novel xenograft tumor model, in which tumors are established under non-induced conditions, followed by induced target inactivation upon oral dosing of the inducer. Three genes were evaluated, a known oncogene (mTOR), and two novel cancer targets (HE7 and HE26), by assessing the tumor response to their silencing.
We demonstrate a significant response of staged tumor regression to silencing of all three target genes. For early staged tumors, inactivation of each of the three targets caused dramatic tumor regression (100% regressed and 50% became tumor-free for both mTOR and HE7, and 100% for HE26). Advanced staged tumors also demonstrated significant responses (100% regression for mTOR, and 75% for HE7, 85% HE26).
Our results demonstrate the utility of this unique and powerful model for efficacy evaluation of cancer targets; our data also provide robust in vivo efficacy validations of HE7 and HE26 as novel cancer therapeutic targets.