Geron Corp (GERN)

[xe2dy]

Geron Presentations on Imetelstat (2nd article)

5/14/09 - Geron Presentations on Imetelstat GRN163L at the AACR 2009 Annual Meeting

2009 MAY 14 - (NewsRx.com) -- Geron Corporation (Nasdaq:GERN) announced five presentations were given during the Annual Meeting of the American Association for Cancer Research (AACR) in Denver, CO. The presentations focused on the activity of Gerons telomerase inhibitor, imetelstat sodium (GRN163L), against cancer stem cells from non-small cell lung, breast, pancreatic, prostate, and pediatric neural tumors (see also Geron Corporation).

Geron is currently testing imetelstat (GRN163L) in six clinical trials recruiting from 22 U.S. medical centers, examining the safety, pharmacokinetics and pharmacodynamics of the drug, alone or in combination with standard therapies, in solid tumors, chronic lymphoproliferative diseases, multiple myeloma, lung and breast cancers. The trials continue to recruit patients and dose escalation continues beyond the levels at which telomerase inhibition was first detected clinically.

At last years ASH meeting, we presented the first clinical evidence of telomerase inhibition in patients treated with imetelstat in our ongoing single agent Phase I trial in multiple myeloma. Telomerase inhibition was observed not only in the bulk tumor fraction of patients bone marrow, but, importantly, also in the stem cell containing fraction. Telomerase inhibition has also been observed more recently in the bone marrow from additional patients from that single agent trial, said Thomas B. Okarma, Ph.D., M.D., Gerons president and chief executive officer. At AACR we presented data from several preclinical studies that extend this observation to other important tumor types. These are significant findings because cancer stem cells are the small sub-population of cells in a tumor that are believed to be responsible for cancer recurrence due to their resistance to standard treatments. We believe we have a drug with potentially broad anti-cancer stem cell activity. Therapeutic Targeting of Telomerase for Non-Small Cell Lung Cancer Lung cancer is the most frequent cause of cancer-related deaths in the U.S. Telomerase is essential for sustained cell proliferation in a wide range of malignant tumors, including 95% of lung cancers. Imetelstat is currently being tested in a Phase I/II clinical trial for non-small cell lung cancer (NSCLC) in combination with standard treatment (carboplatin and paclitaxel chemotherapy).

Data from a companion preclinical study, presented in a mini-talk by Ms. Robin Frink and colleagues from the University of Texas Southwestern Medical Center, showed that continued treatment of NSCLC cell lines with imetelstat inhibited telomerase activity, induced progressive decreases in telomere length, and resulted in cell death. Treatment with imetelstat over several months showed a dramatic decrease in the ability of NSCLC cell lines to form colonies in culture. In addition, there were marked changes in the expression of genes associated with stem cell proliferation. These findings suggest that targeting telomerase therapeutically will require sustained treatment with imetelstat and also provide preliminary evidence that the putative stem cell component of NSCLC is targeted by the drug. Imetelstat Sodium (GRN163L) Diminishes Self Renewal Capacity and Decreases Tumorigenic Potential of Putative Cancer Stem Cells from Human Breast Cancer and Pancreatic Cancer Cell Lines Data on the effects of imetelstat on putative cancer stem cells from a human breast cancer and a pancreatic cancer cell line were presented in a poster by Dr. Immanual Joseph and other Geron scientists. The data show that the number of putative cancer stem cells in the human breast cancer cell line MCF7 and their ability to self renew (a key characteristic of stem cells) was dramatically diminished after treatment with imetelstat. In studies of the human pancreatic cancer cell line PANC-1, exposure to imetelstat in culture resulted in the reduction of the putative cancer stem cell population and a significant decrease in the ability of these cells to form tumors in mice. The Effects of Telomerase Inhibition on Prostate Tumor-Initiating Cells Prostate cancer is the most common type of cancer in men and has a high morbidity with relatively few chemotherapeutic options for patients with metastatic disease. As in many other cancers, high levels of telomerase activity have also been found in prostate tumors. The data presented at AACR provide a strong rationale for initiating clinical studies of imetelstat in patients with prostate cancer.

Presented in a poster by Dr. Calin Marian and colleagues from the University of Texas Southwestern Medical Center, studies of four human prostate cancer cell lines demonstrated that, as in all tumor types tested to date, the high levels of telomerase activity in these cell lines can be inhibited by imetelstat and that continued treatment led to telomere shortening and a decreased proliferation potential in culture. Once a sufficient shortening of the telomeres was achieved by sustained exposure to imetelstat, the prostate cancer cell lines tested showed an increased sensitivity to the standard chemotherapeutic agents, docetaxel and doxorubicin. Long-term exposure to imetelstat also resulted in a progressive and dramatic depletion of the ability of prostate cancer cell lines to form colonies in vitro, evidence for activity against prostate cancer stem cells.

Putative cancer stem cells, also called tumor-initiating cells, isolated from the prostate cancer cell lines using two different methods (either expression of specific cell surface markers or by dye exclusion properties) were found to have similar levels of telomerase activity to the bulk population and that activity could be inhibited by imetelstat. In addition, the average telomere length of the putative cancer stem cells was similar to the main population and telomerase inhibition led to shortening of telomeres in both populations. Biologic and Therapeutic Role of Telomere Maintenance in Pediatric Neural Tumor Initiating Cells Pediatric neural tumors (PNT), comprising childhood CNS tumors and neuroblastoma, are the leading cause of morbidity and mortality among childhood cancers. Telomerase activity can predict survival in PNT and it has been shown that in gliomas and neuroblastomas telomere maintenance governs the unique tendency of PNT to undergo spontaneous growth arrest on the one hand or recur despite maximal resection and chemo-radiation therapies on the other.

Data on the effect of imetelstat on glioma and neuroblastoma-derived cell lines with stem cell-like characteristics were presented in a poster by Dr. Cindy Zhang and colleagues at the Arthur and Sonia Labatt Brain Tumor Research Center and the Research Institute of the Hospital for Sick Children in Toronto in collaboration with Geron scientists. The data show that telomerase is only active in the subpopulation of the neural tumor cells with stem cell characteristics (self-renewal). In such cell lines derived from both glioblastoma and neuroblastoma, treatment with imetelstat resulted in an inhibition of telomerase, a loss of replicative potential, a progressive shortening of telomeres and cell senescence. In addition, cells that were pre-treated with imetelstat were more sensitive to radiation than untreated cells in vitro. Telomere Shortening in Human Tumor Cells In Vitro and In Vivo Following Treatment With Telomerase Inhibitor Imetelstat (GRN163L) Presented in a poster by Dr. Ekatarina Bassett and colleagues at Geron with collaborators at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, an alternative and more sensitive PCR-based method (STELA Single Telomere Length Assay) was used to monitor changes in telomere length in a range of human tumor cells after treatment with imetelstat. Conventional assays (e.g., TRF) tend to underestimate the calculated length of short telomeres and many thousand fold more cells are required to see short telomere populations, whereas STELA enables more precise and sensitive monitoring of short telomere changes.

Using STELA, telomere shortening was observed after treatment with imetelstat in a NSCLC cell line after continuous treatment in culture and in xenograft tumors in treated mice. The onset of telomere shortening was found to be gradual and resulted in an accumulation of shorter telomeres compared to untreated controls. Also using STELA, telomere shortening in myeloma cells was found to be induced by imetelstat treatment in both the bulk and stem cell fractions. Furthermore, telomere shortening in unsorted myeloma cells exposed to imetelstat correlated closely with a reduction in the ability of the cells to form colonies. Finally, STELA was used to detect the distribution in telomere length in primary human tissues (peripheral blood, hair follicles and bone marrow) to demonstrate the potential for this assay to monitor samples from patients treated with imetelstat.

About Telomerase and Imetelstat (GRN163L)

Telomerase is a critical and potentially broadly applicable tumor target. The enzyme is expressed in a wide range of malignant tumors, and its activity is essential for the indefinite replicative capacity of cancer cells that enables their malignant cell growth. Telomerase is absent or expressed only transiently at low levels in most normal adult tissues.

Imetelstat is a short chain oligonucleotide that binds with high affinity and specificity to the catalytic site of telomerase, resulting in competitive inhibition of enzyme activity. Proprietary manufacturing chemistry and the addition of a 5' lipid chain have enabled the molecule to penetrate cells and tissues throughout the body.

Imetelstat has demonstrated anti-tumor effects in a wide range of preclinical models of hematological and solid tumors and is being tested in multiple clinical trials. Preclinical studies have also demonstrated that imetelstat can inhibit clonogenic growth of both primary myeloma patient samples and subpopulations from myeloma cell lines enriched for cancer stem cells. These subpopulations show resistance to several conventional agents, including bortezomib. Cancer stem cells capable of clonogenic growth may play an important role in rapid regrowth of tumors after initial reduction by standard treatments.

http://www.pharmacychoice.com/news/article.cfm?Article_ID=396002