9/25/2013 10:00:18 AM
LA JOLLA, Calif., September 25, 2013 – A new experimental approach to treating a type of
brain cancer called medulloblastoma has been developed by researchers at Sanford-
Burnham Medical Research Institute (Sanford-Burnham). The method targets cancer
stem cells—the cells that are critical for maintaining tumor growth—and halts their
ability to proliferate by inhibiting enzymes that are essential for tumor progression. The
process destroys the ability of the cancer cells to grow and divide, paving the way for a
new type of treatment for patients with this disease.
The research team, led by Robert Wechsler-Reya, Ph.D., professor in Sanford-
Burnham’s NCI-Designated Cancer Center and director of the Tumor Initiation and
Maintenance Program, discovered that the medulloblastoma cancer cells responsible for
tumor growth and progression (called cancer stem cells or tumor-propagating cells—
TPCs) divide more quickly than normal cells. Correspondingly, they have higher levels
of certain enzymes that regulate the cell cycle (Aurora and Polo-like kinases). By using
small-molecule inhibitors to stop the action of these enzymes, the researchers were able
to block the growth of tumor cells from mice as well as humans. The research findings
are described in an online paper published September 25 by Cancer Research.
“One tumor can have many different types of cells in it, and they can grow at different
rates. By targeting fast-growing TPCs with cell-cycle inhibitors, we have developed a
new route to assault medulloblastoma. In this study, we have shown that cell-cycle
inhibitors essentially block medulloblastoma tumor progression by halting TPC
expansion, and have opened the window to preventing cancer recurrence,” said
For their research, the scientists tested the effectiveness of cell-cycle inhibitors in a
specific type of brain cancer called Sonic Hedgehog (SHH)-associated medulloblastoma.
These cancers have mutations in components of the SHH pathway that regulate cell
growth during normal development. The mutations cause cell signaling to go awry,
triggering the creation of cancer cells that grow uncontrollably and establish tumors.
SHH-associated tumors account for 25 percent of all human cases of medulloblastoma,
and the SHH pathway has been implicated in other tumor types such as lung, breast,
prostate, and skin cancer.
“Our increased understanding of SHH-associated tumors has recently led to the
development of drugs that specifically inhibit the SHH pathway. Early studies in
humans with these new drugs have offered some hope for patients, but many do not
respond and most patients who do respond develop resistance to the drug. For this
reason, it is essential to develop alternative, or additional, therapies that are more
effective than current treatment options,” Wechsler-Reya said.
The team’s first set of experiments used a mouse model for SHH-dependent
medulloblastoma. In-vitro studies of mouse tumor cells showed that cell-cycle
inhibitors caused tumor cell death. In vivo, mice that were treated with the inhibitor
had smaller tumors that weighed less compared to mice that were not treated,
essentially halting the progression of the tumor.
The second set of experiments used human SHH-dependent medulloblastoma cells.
When the researchers treated these human tumor cells with cell-cycle inhibitors, they
also observed a significant reduction in tumor growth and progression.
Finally, when the scientists combined SHH inhibitors with cell-cycle inhibitors, they
found that the combination worked together to produce results that were greater than
either inhibitor alone.
“These results strongly support an approach to treatment that combines SHH inhibitors
with cell-cycle inhibitors to treat medulloblastoma. Our hope is that the combination of
these inhibitors will prevent tumor progression and drug resistance, and improve the
overall effectiveness of current treatment options. We look forward to clinical studies in
human medulloblastoma patients as well as other cancers that are suitable for this
approach,” Wechsler-Reya said.
This research was funded by the National Cancer Institute (grant ROI-CA122759) and
the National Institute for Neurological Diseases and Stroke (ROI NSO52323) as well as
pilot funds from Golfers Against Cancer and the Pediatric Brain Tumor Foundation
Institute at Duke University. R.J. Wechsler-Reya is the recipient of a Leadership Award
(CIRM LA-01747) from the California Institute for Regenerative Medicine (San
The study was co-authored by Shirley L. Markant, Sanford-Burnham, Sanford
Consortium for Regenerative Medicine, and Duke University Medical Center; Lourdes
A. Esparza, Sanford-Burnham and Sanford Consortium for Regenerative Medicine;
Jesse Sun, Duke University Medical Center; Kelly L. Barton, Duke University Medical
Center; Lisa M. McCoig, Duke University Medical Center; Gerald A. Grant, Duke
University Medical Center, John R. Crawford, University of California San Diego and
Rady Children’s Hospital, San Diego; Michael L. Levy, University of California San
Diego and Rady Children’s Hospital, San Diego; Paul A. Northcott, German Cancer
Research Center, Heidelberg, Germany and Hospital for Sick Children, University of
Toronto, Toronto, Ontario, Canada; David Shih, Hospital for Sick Children, University
of Toronto, Toronto, Ontario, Canada; Marc Remke, Hospital for Sick Children,
University of Toronto, Toronto, Ontario, Canada; Michael Dr. Taylor, Hospital for Sick
Children, University of Toronto, Toronto, Ontario, Canada; and Robert J. Wechsler-
Reya, Sanford-Burnham, Sanford Consortium for Regenerative Medicine, and Duke
University Medical Center.
Medulloblastoma is the most common malignant brain tumor, affecting about 500
children under the age of 10 in the United States annually. Current treatment options
for medulloblastoma include aggressive surgery, radiation, and chemotherapy. Today,
over two-thirds of children are successfully treated. However, survivors generally
suffer long-term side effects such as cognitive and developmental disabilities due to the
aggressive treatment, and in many cases the tumor reappears within two years after
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the
fundamental molecular causes of disease and devising the innovative therapies of
tomorrow. Sanford-Burnham takes a collaborative approach to medical research with
major programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory,
and childhood diseases. The Institute is recognized for its National Cancer Institutedesignated
Cancer Center and expertise in drug discovery and stem-cell technologies.
Sanford-Burnham is a nonprofit, independent institute that employs 1,200 scientists and
staff in San Diego (La Jolla), California, and Orlando (Lake Nona), Florida. For more
information, visit us at sanfordburnham.org.
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