Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer

Abstract

Telomerase activity is undetectable in most normal tissues but the vast majorities of cancers express active telomerase. Therefore, telomerase serves as an attractive target for the treatment of cancers. GRN163L is a lipid-modified oligonucleotide N3'-->P5' thio-phosphoramidate complementary to the RNA template region of human telomerase. The anti-telomerase activity of GRN163L was evaluated using MDA-MB-231 and MDA-MB-435 human breast adenocarcinoma cell lines. Twice weekly administration of GRN163L resulted in the inhibition of telomerase activity and progressive telomere shortening. Cells treated with GRN163L did not demonstrate decreased cell proliferation for up to 2 weeks. However, after additional treatment, cell proliferation gradually decreased in GRN163L-treated cells compared to untreated or mismatch control oligoncleotide treated cells. Furthermore, anti-tumorigenic effects were seen in cells treated with GRN163L, as cells lose their ability to form colonies in soft agar and were unable to form colonies in the clonal efficiency assay upon incubation with GRN163L. Moreover, breast cancer cells that were treated with GRN163L for only 1 week prior to plating in invasion chambers, and when bulk telomere are still long, exhibit significantly diminished invasive potential. These results reveal critical information regarding the effectiveness of GRN163L as a potential therapeutic agent for the treatment of human breast cancer.

The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

“…41 In brief, 500 cells were plated on 100 mm 2 dishes and grown for 7-11 days. Treatment medium was refreshed every 3 to 4 days.…”

“…11 Studies in various adult and pediatric cancer cell lines have demonstrated that imetelstat, but not a mismatch oligonucleotide control, inhibited cell proliferation, colony formation, and invasiveness. [11][12][13][14][15][16][17][18] Phase 1 and 2 clinical trials demonstrated a favorable pharmacokinetic and side effect profile for imetelstat, though with mixed clinical results. 14,[19][20][21][22][23] Although telomerase activity is regulated largely at the level of transcription of TERT, the gene that encodes the catalytic component of the telomerase enzyme complex, it has become clear that telomerase regulation is complex and also involves posttranslational modifications, alternative splicing, and binding to chaperone proteins.…”

Targeting telomerase for cancer therapeutics

“…GRN163L is a short-chain oligonucleotide that is unique in its resistance to nuclease digestion in blood and tissues and its very high affinity and specificity for telomerase (Dikmen et al, 2005;Herbert et al, 2005;Gellert et al, 2006). The molecule has superior cellular and tissue penetration properties due to the chemistry and a 5 0 lipid chain that facilitates entry into cells.…”

Telomerase and its potential for therapeutic intervention

“…GRN163L (Figure 3a), is a 13-mer oligonucleotide N3 0 -P5 0 thio-phosphoramidate in a lipid carrier (L), which has demonstrated promising preclinical in vitro and in vivo antitumour activity and has just entered clinical trials. GRN163L (Geron Corp., CA, USA) is the first anti-telomerase agent to enter the clinic (Dikmen et al, 2005;Gellert et al, 2006;Jackson et al, 2007). Safety and dose finding studies are underway in patients with refractory and relapsed solid malignancies.…”