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Geron Announces Two Publications Demonstrating That Its Telomerase Inhibitor Drug Targets Cancer Stem Cells

Geron Corporation (Nasdaq:GERN) today announced the publication of preclinical data demonstrating that the company’s telomerase inhibitor drug, imetelstat (GRN163L), currently in Phase 2 clinical trials, targets cancer stem cells from multiple myeloma, pancreatic and breast cancers.

Cancer stem cells, found in many types of cancer, are rare populations of malignant cells with the capacity for endless self-renewal. They are believed to be responsible for tumor growth, recurrence and metastasis. Their resistance to chemotherapy and conventional anti-cancer agents make them important targets for novel therapies.

“These data are significant because they demonstrate that the cancer stem cell population can be targeted by inhibiting telomerase with imetelstat, and that this is associated with a survival benefit in animal models,” said Stephen M. Kelsey, M.D., Geron’s executive vice president and chief medical officer, oncology. “Our Phase 2 clinical program is testing imetelstat in lung cancer, chronic leukemias, breast cancer and multiple myeloma, all malignancies in which cancer stem cells are believed to play an important role in relapse after standard therapy.”

Multiple Myeloma

The first publication shows the inhibitory effect of imetelstat on multiple myeloma cancer stem cells in vitro and in animal models of the human disease. The research, published in the journal PLoS ONE, was co-authored by Dr. William Matsui and colleagues at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and scientists from Geron. The publication is available online at http://dx.plos.org/10.1371/journal.pone.0012487.

The data demonstrate that treatment with the telomerase inhibitor, imetelstat, for two weeks in vivo in a xenograft model of established human multiple myeloma resulted in significant survival benefit compared to controls: 8/8 animals alive in the imetelstat treated group versus 0/8 alive in the control group at day 110.

To determine if the survival benefit was due to targeting of the cancer stem cells, further in vitro and in vivo experiments using cancer stem cells isolated from human multiple myeloma cell lines and primary myeloma patient samples were performed. Cancer stem cells isolated from human multiple myeloma cell lines and treated with imetelstat in vitro showed reduced proliferation with five-fold fewer colonies after treatment for three weeks and 100-fold fewer colonies after five weeks compared to controls. Importantly, similar results were obtained using multiple myeloma stem cells isolated from samples of patient bone marrow, demonstrating that cancer stem cells from the cell lines are representative of the human disease.

Establishment of new tumors in a xenograft model serves as an experimental model of disease recurrence. When myeloma cells were pretreated in vitro with imetelstat for two weeks and subsequently implanted in mice given no further treatment, the development of new tumors was significantly reduced, leading to increased survival of the animals compared to controls implanted with untreated myeloma cells.

Breast and Pancreatic Cancer

The second publication demonstrates the inhibitory effect of imetelstat on cancer stem cells from breast and pancreatic tumor cell lines in vitro and in animal models of the human disease. The data, published in the journal Cancer Research, were co-authored by Geron scientists and Professors Jerry Shay and Woodring Wright at the University of Texas Southwestern Medical Center at Dallas. The abstract of the publication is available on the journal’s website at http://cancerres.aacrjournals.org/content/early/2010/11/04/0008-5472.CAN-10-0233.abstract.

Treatment in vitro of pancreatic and breast cancer cell lines with imetelstat reduced the proportion of cancer stem cells from the bulk tumor populations by 1.6 to 12 fold in all cell lines tested. In addition, imetelstat inhibited the growth of bulk breast cancer cells, resulting in cell death after three weeks of treatment.

A key in vitro characteristic of cancer stem cells is the ability of single breast cancer stem cells to give rise to a sphere of cells called mammospheres, which can subsequently give rise to new mammospheres when dissociated. Imetelstat treatment resulted in a two-fold reduction in the number of new mammospheres formed from single cells and an 8-fold decrease in the number of cells in each mammosphere compared to controls.

Xenograft studies were also performed to assess the impact of imetelstat treatment on breast and pancreatic cancer stem cell function in vivo. Breast or pancreatic cancer cell lines were pre-treated with imetelstat in vitro and implanted into mice. Imetelstat was also administered to these animals for an additional 50 days. Control animals were implanted with untreated cancer cell lines and then given saline. Imetelstat treatment significantly reduced the frequency of tumor formation from implanted pancreatic and breast cancer lines. As expected, tumors were present at day 50 in all of the untreated control animals implanted with pancreatic cancer cells. In contrast, only half of the animals in the imetelstat-treated group had tumors. Similarly, 50 days after implanting the breast cancer cells, tumors were present in 80% of the untreated control group, but in only 40% of the imetelstat group.

Taken together, these two studies demonstrate broad anti-cancer stem cell activity by the telomerase inhibitor, imetelstat, thereby confirming preclinically the anti-cancer stem cell rationale for Geron’s Phase 2 trials in patients with breast cancer and multiple myeloma.

About Telomerase and Imetelstat (GRN163L)

Telomerase is a critical and 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 that enables malignant cell growth. Telomerase has now also been shown to be a target for cancer stem cells. Telomerase is absent or expressed only transiently at low levels in most normal adult tissues.

Imetelstat is a lipidated 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 xenograft models of human solid and hematological tumors, and potent activity against cancer stem cells derived from primary patient samples or cancer cell lines from multiple tumor types.

Imetelstat has been tested in six Geron-sponsored Phase 1 clinical trials at 22 U.S. medical centers treating over 180 patients examining the safety, tolerability, pharmacokinetics and pharmacodynamics of the drug, alone or in combination with other standard therapies, in patients with different hematological and solid tumors.

A randomized Phase 2 clinical trial of imetelstat has been initiated in non-small cell lung cancer. A second randomized Phase 2 trial is planned in breast cancer and two single arm Phase 2 clinical trials are planned in multiple myeloma and essential thrombocythemia.

About Geron

Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes. The company is advancing an anti-cancer drug and a cancer vaccine that target the enzyme telomerase through multiple clinical trials in different cancers. For more information, visit www.geron.com.

This news release may contain forward-looking statements made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that statements in this press release regarding potential applications of Geron’s telomerase technology constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and protection of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Geron’s periodic reports, including the quarterly report on Form 10-Q for the quarter ended September 30, 2010.

Contacts:

Geron Corporation
Anna Krassowska, Ph.D., 650-473-7765
Investor and Media Relations
info@geron.com

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