Geron Announces Publication of Data on its Telomerase Inhibitor in Glioblastoma
News Jan 13, 2010
Geron Corporation has announced the publication of preclinical data demonstrating that its telomerase inhibitor drug, imetelstat (GRN163L), inhibited telomerase activity and reduced tumor size in xenograft models of glioblastoma, and inhibited the activity of glioblastoma stem cells in culture.
The data, authored by Geron collaborators at the University of Texas Southwestern Medical Center at Dallas, were published in the January 1, 2010 issue of Clinical Cancer Research.
"We are excited by the telomerase inhibition observed in the glioblastoma model. The blood-brain tumor barrier limits the delivery of most therapeutic drugs to brain tumors, but these data show that imetelstat penetrates that barrier," said Thomas B. Okarma, Ph.D., M.D., Geron's president and chief executive officer. "Cancer stem cells pose an additional therapeutic challenge. These data add to the growing list of cancer types where the inhibition of cancer stem cells by imetelstat has been shown preclinically. We will further investigate imetelstat's anti-cancer stem cell potential clinically in our Phase II trials in breast and lung cancers, multiple myeloma and chronic leukemias that will begin later this year."
Recent evidence suggests that glioblastomas contain rare populations of cells with a capacity for endless self-renewal, known as cancer stem cells or tumor initiating cells, and may be responsible for tumor growth and recurrence. Cancer stem cells also show resistance to many conventional anti-cancer agents and are therefore important targets for novel therapies.
Glioblastoma tumor initiating cells isolated from patient samples can be propagated indefinitely in vitro, maintaining the molecular properties of the original tumor. The current data show that the clonogenic and proliferative capacity of primary human glioblastoma tumor initiating cells is vastly decreased by exposure to imetelstat in vitro, compared to controls. Telomerase activity and telomere length were reduced, ultimately leading to cell death.
In addition, temozolomide and ionizing radiation, standard treatment regimens for glioblastoma after surgical resection, boost the effects of imetelstat, further decreasing the viability of cultured glioblastoma tumor initiating cells.
Orthotopic tumors were established by implanting glioblastoma tumor initiating cells into the brains of mice. Telomerase was inhibited by 60-70% in these tumors within 3-5 days after administering imetelstat intraperitoneally (into the body cavity). This is an important observation demonstrating that imetelstat can penetrate the blood-brain tumor barrier, unlike many chemotherapeutic agents.
Further in vivo animal data using a subcutaneous tumor model showed that imetelstat treatment led to a significant decrease in tumor growth rate and a 10-fold decrease in tumor size after 53 days of treatment compared to the vehicle control treated group.
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