Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to 
be responsible for the maintenance and recurrence of cancer and metastasis. 
Telomerase is constitutively active in both bulk tumor cell and CSC populations 
but has only limited expression in normal tissues. Thus, inhibition of 
telomerase has been shown to be a viable approach in controlling cancer growth 
in nonclinical studies and is currently in phase II clinical trials. In this 
study, we investigated the effects of imetelstat (GRN163L), a potent telomerase 
inhibitor, on both the bulk cancer cells and putative CSCs. When breast and 
pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase 
activity in the bulk tumor cells and CSC subpopulations were inhibited. 
Additionally, imetelstat treatment reduced the CSC fractions present in the 
breast and pancreatic cell lines. In vitro treatment with imetelstat, but not 
control oligonucleotides, also reduced the proliferation and self-renewal 
potential of MCF7 mammospheres and resulted in cell death after <4 weeks of 
treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in 
nude mice, concomitant with a reduction in the CSC levels. Differences between 
telomerase activity expression levels or telomere length of CSCs and bulk tumor 
cells in these cell lines did not correlate with the increased sensitivity of 
CSCs to imetelstat, suggesting a mechanism of action independent of telomere 
shortening for the effects of imetelstat on the CSC subpopulations. Our results 
suggest that imetelstat-mediated depletion of CSCs may offer an alternative 
mechanism by which telomerase inhibition may be exploited for cancer therapy.