Geron Corporation (Nasdaq:GERN) today announced several presentations at the American Association for Cancer Research (AACR) Special Conference on The Role of Telomeres and Telomerase in Cancer Research held in Fort Worth, TX between February 27th and March 1st. The conference comprised ten scientific sessions with over fifty oral presentations. Geron scientists and collaborators presented recent data on the company’s telomerase inhibitor, imetelstat sodium (GRN163L), and highlighted the drug’s activity against cancer stem cells.
“Our telomerase inhibitor is showing anti-cancer stem cell activity in a range of preclinical models. In our Phase II trials of imetelstat starting this year we are targeting malignancies that are thought to be driven, at least in part, by cancer stem cells.”
“This AACR Special Conference underscores the importance of telomerase as a cancer target. What has emerged from recent preclinical studies is a growing body of evidence that telomerase is not only a broad cancer target, but a target for cancer stem cells,” said Stephen M. Kelsey, M.D., Geron's executive vice president and chief medical officer, oncology. “Our telomerase inhibitor is showing anti-cancer stem cell activity in a range of preclinical models. In our Phase II trials of imetelstat starting this year we are targeting malignancies that are thought to be driven, at least in part, by cancer stem cells.”
Cancer stem cells are small populations of cells within tumors believed to be responsible for initiating tumor growth, recurrence and metastasis. Cancer stem cells are capable of indefinite self-renewal, because of high telomerase activity, and can differentiate into all cells found in a particular tumor type. Cancer stem cells show resistance to standard chemotherapeutic agents that are effective against bulk tumor cells. After initial reduction of a tumor by standard treatments, the tumor may re-grow as a result of cancer stem cell proliferation and differentiation, causing relapse of the disease. Cancer stem cells are therefore important targets for novel therapies.
Keynote Presentation: Targeting Telomerase for Cancer Therapeutics
The Keynote presentation entitled: “Targeting Telomerase for Cancer Therapeutics” was delivered by Geron collaborator Prof. Jerry W. Shay at the University of Texas, Southwestern in Dallas, and centered on imetelstat. Prof. Shay presented data from his preclinical work on the anti-tumor effects of the drug in xenograft models of human cancers and its activity against cancer stem cells. The presentation included data published in Clinical Cancer Research in January demonstrating imetelstat’s in vitro and in vivo efficacy against glioblastoma stem cells and the drug’s ability to penetrate the blood-brain tumor barrier in an orthotopic xenograft model.
In Vivo and In Vitro Inhibition of Multiple Types of Cancer Stem Cells by the Novel Telomerase Inhibitor Imetelstat
Geron scientists and collaborators summarized a number of preclinical study results showing the efficacy of imetelstat against cancer stem cells from multiple tumor types. Imetelstat exhibits potent activity against cancer stem cells derived from primary patient samples and cancer cell lines from myeloma, melanoma, breast, pancreatic, pediatric glioma, neuroblastoma and glioblastoma. The data show that imetelstat inhibits in vitro cell proliferation and the growth of cancer stem cells, including their ability to form colonies. Imetelstat treatment also reduced the ability of cancer stem cells to form tumors in xenograft models.
Tumor Initiating Cells: A Subpopulation of Tumor Cells That Can Be Safely Targeted for Telomerase Inhibition
Dr. Uri Tabori and colleagues at the Arthur and Sonia Labatt Brain Tumor Research Center of the Hospital for Sick Children in Toronto, in collaboration with Geron scientists, presented data on pediatric neural tumor stem cells.
Prior work has shown that telomerase activity can predict survival in patients with pediatric neural tumors and Dr. Tabori and colleagues have demonstrated that in gliomas and neuroblastomas, telomere maintenance governs the unique tendency of these tumors to either undergo spontaneous growth arrest or to recur despite maximal resection and chemo-radiation therapies. Their work has also shown that telomerase is only active in the subpopulation of neural tumor cells with stem cell characteristics and that glioblastoma and neuroblastoma-derived cancer stem cell lines treated with imetelstat showed inhibition of telomerase, loss of replicative potential, progressive shortening of telomeres and cell senescence.
Data presented at the AACR Special Conference extended these in vitro findings to xenograft models of neuroblastoma. Compared to controls, imetelstat treatment reduced the initiation and growth of tumors in mice and led to increased survival of the animals. When tumor cells were taken from the mice and grown in vitro, the number of colonies formed was significantly reduced in the groups that had been treated with imetelstat compared to non-treated controls. Colony formation is used as an indirect measure of the metastatic potential of tumors. These preclinical data show that inhibiting telomerase with imetelstat in neuroblastoma stem cells reduces tumor growth and increases survival, providing a rationale for the use of imetelstat in pediatric neural tumors, the leading cause of morbidity and mortality among childhood cancers.
Telomerase Inhibitor Imetelstat Sensitive and Resistant Response Phenotypes in Non-Small Cell Lung Cancer
Lung cancer is the most frequent cause of cancer-related deaths in the U.S., and telomerase is essential for sustained cell proliferation in virtually all lung cancers. A Geron-sponsored randomized Phase II clinical trial of imetelstat maintenance after first-line induction chemotherapy for non-small cell lung cancer (NSCLC) will be initiated this year.
Preclinical study data presented 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 decreases in telomere length, and slowed cell growth rates in vitro in most cells lines tested.
In Vivo Treatment With Imetelstat Inhibits Telomerase in Xenograft Tumors, Mouse Bone Marrow, PBMC and Hair Follicles
The final presentation on imetelstat was by Geron scientists and collaborators at the University of Chicago Medical Center and Barbara Ann Karmanos Cancer Center.
Imetelstat has been shown to inhibit telomerase activity and reduce tumor growth in multiple xenograft models of human cancer in a dose-dependent fashion. Data from interim pharmacokinetic analyses in the ongoing Phase I trial of imetelstat in patients with solid tumors demonstrate that plasma concentrations of the drug achieved in patients are higher than plasma concentrations at which efficacy is observed in animal models. In addition, preliminary pre- and post-treatment analyses of target and surrogate patient tissue samples (bone marrow, peripheral blood mononuclear cells and hair follicles) from the Phase I trials in solid tumors, multiple myeloma and chronic lymphoproliferative disease have shown telomerase inhibition.