Scientists at St. Jude
Children's Research Hospital have demonstrated in a mouse model a new,
locally applied treatment for the eye cancer retinoblastoma that not only
greatly reduces the size of the tumor, but does so without causing the side
effects common with standard chemotherapy. The treatment also appears to be
suitable for certain forms of breast, lung, prostate and colon cancer, and
is simple enough for widespread use even in countries with limited
resources.
A report on this work appears in the Nov. 2 issue of the journal
Nature.
Retinoblastoma occurs in about 5,000 young children worldwide each
year, arising from the immature retina -- the part of the eye responsible
for detecting light and color. The cancer is fatal if left untreated.
The new treatment is based on an earlier discovery at St. Jude which
overturned a widely held belief about the process of apoptosis (cell
suicide) in retinoblastoma, according to Michael Dyer, Ph.D. He is a Pew
Scholar and associate member of the St. Jude Department of Developmental
Neurobiology. Apoptosis is the way the body rids itself of abnormal cells
that might become cancerous or cause other problems.
Until now, retinoblastoma experts thought that a mechanism called the
p53 pathway triggered apoptosis in other types of cancer cells but not in
retinoblastoma. The St. Jude team not only proved that the p53 pathway was
activated in early stage retinoblastoma, but that excessive levels of a
molecule called MDMX blocked it from triggering apoptosis in more advanced
tumors. Based on this discovery, the St. Jude team used a molecule called
nutlin-3 to block MDMX in retinoblastoma cells in test tube studies as well
as in mouse models. The molecule was originally developed by Roche
Pharmaceuticals (Nutley, N.J.) for a similar use against a related target
called MDM2 in adult cancer cells.
The success in knocking out MDMX with nutlin-3 represents the first
example of local delivery of a targeted chemotherapy drug for any childhood
cancer, Dyer said.
After demonstrating the effectiveness of locally applied nutlin-3, the
team combined it with topotecan, a drug also being investigated in the
treatment of retinoblastoma. Local delivery of this two-drug targeted
treatment was even more effective, reducing tumor size significantly more
than the most effective known combination of standard chemotherapy drugs.
"Our finding with locally applied nutlin-3 also has major implications
for certain forms of adult cancers, since some forms of breast, lung,
prostate and colon cancer are caused by abnormally large quantities of
MDMX," Dyer explained. "So knocking out MDMX in those cancers might also
dramatically reduce tumor size."
This work is likely to have its biggest impact on the care of children
with retinoblastoma internationally, added Carlos Rodriguez-Galindo, M.D.,
associate member of the St. Jude Oncology department.
"Ideally, these treatments could be administered even in countries that
cannot afford the highly complex infrastructure now required to manage
children with retinoblastoma," added Matthew Wilson, M.D., a surgeon in the
St. Jude Ophthalmology division and co-author of the paper.
Other authors of the paper include Nikia Laurie and Stacy Donovan, co-
first authors who contributed equally to this work; Chie-Schin Shih, Jiakun
Zhang, Nicholas Mills, Christin Fuller, Adithi Mohan and R. Kiplin Guy (St.
Jude); Amina Teunisse, Suzanne Lam, Yolande Ramos and Aart G. Jochemsen
(Leiden University Medical Center, the Netherlands); Dianna Johnson
(University of Tennessee, Memphis); Micaela Quarto (FIRC Institute of
Molecular Oncology, Milan, Italy); Sarah Francoz and Jean-Christophe Marine
(Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium); and
Susan M. Mendrysa (Purdue University, West Lafayette, Ind.).
This work was supported in part by the National Institutes of Health,
Cancer Center Support from the National Cancer Institute, the American
Cancer Society, Research to Prevent Blindness, the Pearle Vision
Foundation, the International Retinal Research Foundation, the European
Community, the Association for International Cancer Research, the Dutch
Cancer Society, the Belgian Foundation Against Cancer, Televie and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for
its pioneering work in finding cures and saving children with cancer and
other catastrophic diseases. Founded by late entertainer Danny Thomas and
based in Memphis, Tenn., St. Jude freely shares its discoveries with
scientific and medical communities around the world. No family ever pays
for treatments not covered by insurance, and families without insurance are
never asked to pay. St. Jude is financially supported by ALSAC, its
fund-raising organization. For more information, please visit stjude.
St. Jude Children's Research Hospital
stjude/