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Telomerase Inhibitor Drug - GRN163L
We have designed and synthesized a special class of short-chain nucleic acid molecules, known as oligonucleotides, that target the template region, or active site, of telomerase. Our work has focused on two of these oligonucleotides, called GRN163 and GRN163L, and we have demonstrated that they have highly potent telomerase inhibitory activity at very low concentrations in biochemical assays, various cellular systems, and animal studies. Our compounds GRN163 and GRN163L are direct enzyme inhibitors, not antisense compounds. They are smaller (lower molecular weight) than typical antisense compounds or other oligonucleotide drug candidates, and we expect them to be administered either locally or systemically. In vitro and in vivo studies indicate that the compounds do not inhibit other critical nucleic acid-modifying enzymes and do not appear to be toxic to normal cells at concentrations expected to inhibit telomerase in tumor cells. Both compounds use a special thiophosphoramidate chemical backbone, for which we acquired key patents in March 2002 from Lynx Therapeutics. We and our collaborators have tested GRN163 in vitro on 14 different cancer cells and demonstrated significant inhibition of telomerase activity in all of them. Research by our collaborators has shown that these compounds inhibit the growth of malignant human glioblastoma (brain cancer) cells, prostate cancer cells, lymphoma, multiple myeloma, hepatocellular carcinoma (liver cancer), melanoma, lung, breast, ovarian and cervical cancer cells in animals. GRN163L is a novel lipid-based conjugate of Geron's first-generation anti-cancer drug, GRN163. GRN163L is a 13-mer oligonucleotide N3' --> P5' thio-phosphoramidate (NPS oligonucleotide) that is covalently attached to a C16 (palmitoyl) lipid moiety. The oligonucleotide backbone leads to improved stability against degradation and improved binding to target sequences compared to other oligonucleotide chemistry. Moreover, GRN163L does not exhibit antisense activity (binding to messenger RNA), but rather directly bind to the RNA component of telomerase at the active site of the enzyme, thereby acting like a conventional pharmaceutical drug. GRN163L has been characterized preclinically and shown to inhibit telomerase in human tumor cells of many cancer types (including lung, breast, prostate, liver, and early stage of human breast cancer), in both cell culture systems and animal models. Studies of this agent alone, and in combination with chemotherapeutic agents, indicate the importance of telomerase as a target for the treatment of cancer, and the potential utility of GRN163L in the treatment of patients with hematologic and solid tumor malignancies After completing a series of animal toxicology and preclinical efficacy studies of GRN163L in 2005, we prepared and submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) to begin human clinical trials of GRN163L in patients with chronic lymphocytic leukemia (CLL). We received FDA concurrence to begin human studies and are currently enrolling patients in this study. In 2006, under our existing GRN163L IND, we initiated a second Phase I study in patients with solid tumor cancers. At the end of 2006, we presented data at two international cancer meetings on the low-dose cohorts of these studies. The data did not identify specific safety issues that precluded testing at higher doses and demonstrated the expected pharmacokinetic properties after multiple intravenous infusions of the drug. We also presented important new data showing that GRN163L is active against tumor stem cells taken from patients with multiple myeloma. Based on this finding, as well as data showing synergy between GRN163L and a drug widely used to treat multiple myeloma, we initiated an additional Phase I study of GRN163L as a single agent in multiple myeloma in 2007. We also initiated a Phase I study in non-small cell lung cancer in 2007, testing GRN163L in combination with standard regimens of paclitaxel/carboplatin. This lung cancer trial is the first to study GRN163L in combination with standard chemotherapy. Currently, there are 15 medical centers enrolling patients in the four clinical trials testing GRN163L. Click here for clinical trial information. |
Telomerase activity is necessary for most cancer cells to replicate indefinitely and thereby enable tumor growth and metastasis. One of our strategies for the development of anti-cancer therapies is to inhibit telomerase activity in cancer cells. Inhibiting telomerase activity should result in telomere shortening and therefore cause degeneration and death of cancer cells. Recent data show that telomerase can protect tumor cells from genomic instability and other forms of cellular stress, suggesting that inhibiting telomerase can cause a more rapid suppression of tumor growth than predicted by telomere loss alone. Because telomerase is expressed at very low levels, if at all, in most normal cells, the telomerase inhibition therapies described below are not expected to be toxic to normal cells. 
