Geron Announces Publication Demonstrating Activity of Imetelstat Against Cancer
Stem Cells From Pediatric Neural Tumors
MENLO PARK, Calif., Jan 10, 2011 (BUSINESS WIRE) -- Geron Corporation (GERN)
today announced the publication of preclinical data demonstrating that the
company's telomerase inhibitor drug, imetelstat (GRN163L), currently in Phase 2
clinical trials, selectively targets cancer stem cells in pediatric tumors of
neural origin.
"Cancers of the brain and nervous system are the most common solid tumors in
children and the leading cause of morbidity and death from pediatric cancers.
These preclinical data show that imetelstat specifically targets the cancer stem
cells in pediatric neural tumors, which we believe may be responsible for
progression and recurrence of the disease," said Stephen M. Kelsey, M.D., Geron's
executive vice president and chief medical officer, oncology. "The findings are
important and support the rationale for conducting a clinical trial in pediatric
tumors."
Telomerase activity has previously been linked to progression and poor patient
survival in childhood cancers of the central and peripheral nervous system, such
as gliomas and neuroblastomas. Cancer stem cells are believed to be responsible
for the growth, recurrence and metastasis of tumors. Cancer stem cells are rare
populations of malignant cells with the capacity for endless self-renewal found
in many types of cancer including neural tumors. Their resistance to chemotherapy
and conventional anti-cancer agents make them important targets for novel
therapies.
The data in the current study showed that telomerase activity was confined to the
cancer stem cell population in the pediatric neural tumors studied. Gliomas
removed from fourteen patients showed high telomerase activity in the cancer stem
cell fraction, but not in the bulk tumor cells. Glioma and neuroblastoma cancer
stem cells grown in culture were also found to have high telomerase activity.
These cancer stem cells were found to have extremely short telomeres, which along
with high telomerase levels, might render them particularly sensitive to
telomerase inhibition by imetelstat.
Treatment of glioma and neuroblastoma cancer stem cell lines with imetelstat for
five to 15 weeks in vitro led to telomerase inhibition, telomere attrition,
growth arrest and loss of self-renewal capacity (a characteristic of stem cells)
compared to untreated controls. Furthermore, growth rate and self-renewal
capacity did not recover after imetelstat treatment was discontinued for seven
weeks despite rapid restoration of telomerase activity. This is significant
because many brain tumors recur after cessation of standard therapy.
In vivo, tumors failed to develop when neuroblastoma cancer stem cells were
pre-treated with imetelstat in vitro for four weeks and subsequently implanted in
mice given no further treatment. Tumors developed if neuroblastoma stem cells
that had not been pre-treated were implanted in mice given imetelstat at the time
of implanting. However, the resulting tumors were approximately 2-3 times smaller
than controls and survival of these animals was improved. These xenograft data
demonstrate activity of imetelstat against neuroblastoma stem cells in vivo. A
third group of mice were treated with imetelstat once tumors were already
established.
Although no survival benefit was observed in these animals, importantly, cells
isolated from those tumors formed 4-5 fold fewer colonies in vitro compared to
controls, showing a decreased self-renewal capacity. Self-renewal of cancer stem
cells is thought to be a key driver of tumor recurrence. These data provide
non-clinical support for the use of imetelstat in combination with tumor
de-bulking agents or as maintenance therapy after tumor de-bulking.
In the past, the feasibility of targeting telomerase in children has been
questioned due to speculation on possible detrimental effects on nervous system
development and maintenance if telomerase activity was required by normal tissue
stem cells in the pediatric nervous system. However, evaluation of normal stem
cells from human fetal or pediatric tissues of neural origin in this study showed
no detectable telomerase activity. Furthermore, normal pediatric neural tissue
stem cells have very long telomeres. Treatment with imetelstat did not affect the
proliferative capacity of these cells even after prolonged exposure. These
significant non-clinical observations support the use of a telomerase inhibitor
to treat childhood cancers.
The research was published online on January 5, 2011 in the journal Clinical
Cancer Research and featured in the journal's editorial CCR Translation section.
The study was co-authored by Dr. Uri Tabori and colleagues at The Hospital for
Sick Children and the University of Toronto, Canada in collaboration with Geron
scientists. The publication is freely available on the journal's website at
clincancerres.aacrjournals.org.
About Telomerase
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.
About Imetelstat (GRN163L)
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.
Two randomized Phase 2 clinical trials of imetelstat have been initiated; the
first in non-small cell lung cancer and a second was recently initiated in breast
cancer. Single arm Phase 2 clinical trials are open in multiple myeloma and
essential thrombocythemia. All are malignancies in which cancer stem cells are
believed to play an important role in relapse after standard therapy. For further
information about clinical trials using imetelstat, please visit
clinicaltrials.gov.
About Geron
Geron is developing first-in-class biopharmaceuticals for the treatment of cancer
and chronic degenerative diseases. The company is advancing anti-cancer therapies
through multiple Phase 2 clinical trials in different cancers by targeting the
enzyme telomerase and with a compound designed to penetrate the blood-brain
barrier (BBB). The company is developing cell therapy products from
differentiated human embryonic stem cells for multiple indications, including
central nervous system (CNS) disorders, heart failure, diabetes and
osteoarthritis, and has initiated a Phase 1 clinical trial in spinal cord injury.
For more information, visit geron.com, visit 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 and oncology 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 and the annual report on Form 10-K for the year ended December
31, 2009.
SOURCE: Geron Corporation
Geron Corporation
Anna Krassowska, Ph.D., 650-473-7765
Investor and Media Relations
info@geron.com |
