GRN163L Inhibits Telomerase Activity in B-CLL Cells.

Abstract

B-CLL cells, like many solid and hematologic malignancies, are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We and others have documented that CLL patients in poorer prognosis subsets, i.e., those without IgVH mutations, had shorter mean telomere lengths and higher telomerase levels than patients with IgVH mutations (Damle et al, 2004; Keating et al, 2003; Bechter et al 1998, Hultdin et al, 2003). Treatment with the telomerase inhibitor GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human hepatoma (Djojosubroto et al, 2005), ovarian carcinoma (Ertem et al, 2004, 2005), and multiple myeloma (CAG, MM.1S) cell lines in vitro and in vivo (AACR 2004 and 2005 Annual Meetings). Although no validated human B-CLL xenograft models exist, preliminary data indicate effective inhibition of telomerase in freshly thawed B-CLL cells upon exposure to GRN163L. We will present data demonstrating robust uptake of GRN163L into primary B-CLL patient cells, along with the subcellular distribution of the oligonucleotide into cytoplasmic and nuclear compartments. Comparison of the effect of GRN163L and a mismatch oligonucleotide control on telomerase inhibition will be described. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005.

The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation

“…GRN163L (Imetelstat) is the most promising oligonucleotide possessing the ability to block telomerase by acting as a complementary sequence to hTERC. In an in vitro study, GRN163L showed effective inhibition of telomerase and of cell growth in B-CLL cells and tumor initiating B cells of patients with multiple myeloma (MM) [ 78 ],[ 79 ]. GRN163L has been entered into stage I and II clinical trials in patients with refractory and relapsed MM and some types of solid tumors.…”