Errant neuro-developmental gene responsive to a potent vitamin A derivative -
A gene that's normally silenced after contributing to brain development was found to be expressed in cells from
medulloblastoma, the most common form of pediatric brain malignancy in children, scientists report in an article published in
the February 1 issue of the journal Cancer Research.
In their study, the scientists discovered that multiple extra copies of the gene, called OTX2, had been switched back on
among tumor cells removed from patients with medulloblastoma brain tumors. In the United States, medulloblastoma accounts for
approximately 30 percent of all pediatric brain tumors.
Further, the scientists discovered that a potent derivative of Vitamin A, known as all trans-retinoic acid or ATRA,
suppressed growth and induced cell death among the OTX2-laden tumor cells. More than half of medulloblastomas grown in the
laboratory responded to ATRA treatment.
"The response that ATRA imposes upon these medulloblastoma brain tumor cell lines suggests that this type of tumor may
respond favorably to ATRA-based therapy," said Hai Yan, M.D., Ph.D., the principle investigator of the study at the Brain
Tumor Center at the Duke University Medical Center.
"ATRA is already clinically approved for the treatment of acute promyelocytic leukemia. These studies lay the conceptual and
practical framework for clinical trials using ATRA in the treatment of a commonly lethal pediatric disease."
Yan said that the OTX2 gene normally contributes to development and growth of certain areas of the brain, such as the
cerebellum, but the gene is generally turned off and no longer used after birth.
Using a novel technique that involves snipping apart the entire DNA content in the chromosomes of medulloblastoma cells and
then analyzing the quantity of each, Yan and his colleagues detected an abnormally amplified segment among the tumor cells on
chromosome 14.
"There was a striking amplification of genetic coding representing a 28-fold increase in base pairs of DNA in that specific
region of chromosome 14," Yan said. The researchers identified OTX2 as the only gene contained within the amplified region of
the chromosome.
The scientists also determined that 60-70 percent of the medulloblastoma cells were churning out large numbers of messenger
RNA specific for OTX2, compared to normal cells which generally show no activity for this gene.
This latter finding suggested another approach, RNA interference, to blocking OTX2 activity. Discovered in the late 90's, RNA
interference or RNAi refers to the introduction of double-stranded RNA (dsRNA) into a cell, where it induces the degradation
of complementary messenger RNA, thereby suppressing the gene expression.
"In our studies, we applied several specifically designed RNAi to the tumor cells that expressed OTX2," Yan said. "We then
observed that the RNAi knocked down OTX2 expression and killed the tumors cells which expressed OTX2. In contrast, the RNAi
did not do any damage to the cells which did not express OTX2."
Among the researchers working with Yan to investigate the OTX2 gene in medulloblastomas were, Chunhui Di, Shaoxi Liao M.D,
Ph.D, David C. Adamson, M.D., Ph.D., Timothy J. Parrett, M.D., Daniel K. Broderick, Qun Shi, Roger E. McLendon, M.D., and
Darell D. Bigner, M.D., Ph.D. from the Brain Tumor Center, Department of Pathology, Duke University Medical Center, Durham,
N.C.; Christoph Lengauer, Ph.D., Jordan M. Cummins, and Victor E.Velculescu, M.D., Ph.D. from The Johns Hopkins University
Medical Institutions, Baltimore, Md.; and Daniel W. Fults, M.D. from the University of Utah School of Medicine, Salt Lake
City, Utah.
This project is supported by The Pediatric Brain Tumor Foundation Institute at Duke, the Duke Brain Tumor SPORE grant from
NCI, Duke Comprehensive Cancer Center Support Grant 5P30CA14236, NIH Grants NS20023-21 and R37CA11898-34, American Brain
Tumor Association, Neurosurgery Research Education Foundation, and grants from the Accelerate Brain Tumor Cure Foundation and
National Cancer Center.
Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory,
translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 other
countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and
advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research;
Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers &
Prevention. AACR's Annual Meeting attracts more than 15,000 participants who share new and significant discoveries in the
cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.
Russell Vanderboom, Ph.D. - vanderboomaacr
American Association for Cancer Research