GERN published (11/11/10) preclinical data demonstrating that its telomerase inhibitor drug, imetelstat (GRN163L) targets cancer stem cells from multiple myeloma, pancreatic and breast cancers in Phase 2 clinical trials.
The 1st publication on Multiple Myeloma 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 data demonstrate that treatment with the telomerase inhibitor, imetelstat, for 2 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 5-fold fewer colonies after treatment for 3 weeks and 100-fold fewer colonies after 5 weeks compared to controls;
- 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 2 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.
The 2nd publication on Breast and Pancreatic Cancer 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.
- 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 2-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;
- Tumors were present at day 50 in all of the untreated control animals implanted with pancreatic cancer cells. In contrast, 1/2 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.
These 2 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.
- 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;
- A 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.”
The Multiple Myeloma publication is available online at http://dx.plos.org/10.1371/journal.pone.0012487.
The Breast and Pancreatic Cancer 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.