Home Medizin Die gezielte Behandlung eines nicht-kodierenden RNA-Abschnitts kann bei Mäusen zur Verkleinerung pädiatrischer Hirntumoren führen

Die gezielte Behandlung eines nicht-kodierenden RNA-Abschnitts kann bei Mäusen zur Verkleinerung pädiatrischer Hirntumoren führen

von NFI Redaktion

According to a new study in mice reported on March 8, targeted treatment of a non-coding RNA segment could help shrink tumors caused by an aggressive type of brain tumor in children, as reported by Cell Reports by researchers at Johns Hopkins Kimmel Cancer Center.

Medulloblastomas are the most common form of malignant brain tumors in children. The most aggressive and difficult-to-treat form of the disease is group 3 medulloblastoma, which is often fatal. The lead author of the study, Ranjan Perera, Ph.D., Director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital in St. Petersburg, Florida, and his colleagues demonstrated an innovative new approach that shrinks group 3 medulloblastoma tumors in mice.

„Group 3 medulloblastomas are very aggressive, and there are currently no targeted therapies,“ says Perera, who mainly works in the Department of Neurosurgery, is a member of the Johns Hopkins Kimmel Cancer Center, and is an Associate Professor of Oncology at the Johns Hopkins University School of Medicine. He is also a lead scientist at the Johns Hopkins All Children’s Hospital Cancer and Blood Disorders Institute and has a secondary affiliation with the hospital’s Institute for Fundamental Biomedical Research. „Our novel therapy based on non-coding RNA could address the urgent need for new therapies for this devastating childhood disease.“

RNA acts as a template for building proteins based on instructions encoded in DNA. Until recently, scientists believed 97% of RNA was „junk“ because only 3% was used to build proteins. However, scientists have realized that non-protein-coding sections of RNA control gene expression. A previous study by Perera and colleagues showed that a long non-coding RNA segment called lnc-HLX-2-7 contributes to the growth of group 3 medulloblastoma tumors by binding to a DNA promoter that increases the expression of cancer-causing genes. Promoters are DNA sections adjacent to non-coding genes that act like switches to turn them on.

The new study provides additional details showing that lnc-HLX-2-7 specifically binds to the HLX promoter region of DNA, increasing HLX gene expression and contributing to tumor growth. HLX triggers tumor growth by binding to promoter regions of several other cancer-causing genes, increasing their expression. One gene whose expression is increased by HLX is MYC, which also increases the expression of several other cancer-causing genes, triggering an activity cascade that accelerates the growth of group 3 medulloblastoma tumors.

Perera and his team developed an intravenous treatment to block the binding of lnc-HLX-2-7 to the HLX promoter, stopping this cascade of cancer gene expression. They assembled a sequence of nucleotides (called antisense oligonucleotides), the building blocks of RNA that can bind to the corresponding nucleotides that lnc-HLX-2-7 is made of, preventing it from binding to the HLX promoter in DNA and leading to its destruction. They coated the sequence with microscopic particles called cerium oxide nanoparticles to protect the lnc-HLX-2-7 until it reaches its target.

When the team treated a mouse model of group 3 medulloblastoma with the experimental intravenous therapy, it reduced tumor growth by 40-50%. Adding cisplatin, a chemotherapy drug currently used to treat medulloblastomas, along with the new therapy further shrank the tumors and extended the survival of the animals. The combination therapy extended the animals‘ lives by about 84 days, compared to a 44-day extension in survival with lnc-HLX-2-7 alone.

„When you combine the two treatments, you see dramatic effects,“ says Perera.

Perera and his colleagues will collaborate with neurosurgeons from Johns Hopkins to plan human therapy studies to further test their safety and efficacy.

It is extremely important to understand why MYC is elevated in these tumors, and this new link to HLX provides insights that open up new therapeutic possibilities.“


Charles Eberhart, MD, Ph.D., Study Co-Author, Researcher at the Kimmel Cancer Center, Director of Neuropathology and Ophthalmological Pathology, and Professor of Oncology and Pathology at the Johns Hopkins University School of Medicine.

The work was supported by the Schamroth Project funded by Ian’s Friends Foundation, the Hough Family Foundation, the National Institutes of Health (Grant P30 CA006973), the National Cancer Institute (Grant 5P30CA030199, R01NS124668-01A1, and R35NS122339), and a CPRIT Scholar Award from MD Anderson Cancer Center.

Co-authors of the study included Keisuke Katsushima, Kandarp Joshi, Menglang Yuan, Stacie Stapleton, and George Jallo from Johns Hopkins. Other authors came from the University of Delaware, the University of Central Florida, Orlando, Institut Curie at PSL University in Paris, Texas Children’s Cancer Center, Houston, Baylor College of Medicine, Houston, and Columbia University Medical Center, New York.

Source:

Journal Reference:

Katsushima, K., et al. (2024). A Therapeutically Targetable Positive Feedback Loop between lnc-HLX-2-7, HLX, and MYC Promoting Group 3 Medulloblastoma. Cell Reports. doi.org/10.1016/j.celrep.2024.113938.

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