Research suggests that a type of non-coding RNA may be useful for categorizing and perhaps even treating one of the four types of medulloblastoma.
Medulloblastoma is the most common malignant brain tumor in children, accounting for about 20% of all pediatric brain cancers. Of the four subtypes, this non-coding RNA is specific only for the sonic hedgehog (SHH) group, which is the most common form in patients younger than 3 years old and accounts for around 30% of all medulloblastomas.
Known as circ_63706, this circular, non-coding RNA represents a previously unknown target associated with SHH-medulloblastoma. The ability to better distinguish between subtypes of medulloblastoma has important implications for developing treatments and improving survival.
The findings are reported in the journal Acta Neuropathologica Communications.
Noncoding RNA, which doesn’t produce proteins, was commonly referred to as “junk RNA” yet it represents 97% of all RNA transcripts in the body. “My lab has been studying these non-coding ‘junk’ RNAs, ‘noise’, or ‘dark matter’ for years,” said senior author Ranjan Perera, Ph.D., director of the Center for RNA Biology and senior scientist at the Cancer & Blood Disorders Institute at Johns Hopkins All Children’s Hospital. “And we want to find drugs or small molecular that can target RNAs which are structurally complex.”
In this paper, Perera and colleagues focused on circular RNAs, which are non-coding RNAs thought to play a role in the development of different types of cancer. Circular RNAs are abundant in the brains of mammals, which makes them potential biomarkers and targets in medulloblastoma and its subtypes. But they contain loops with no free ends—unlike traditional mRNA—which can make them difficult to target. Perera’s team is looking for therapeutic ways to get inside those loops and disrupt their function.
The researchers started by merging a group of publicly available genetic data for 175 samples of medulloblastoma tissue from each of the four classification groups. These included group 3, the most aggressive; group 4, the most common; and Wnt and SHH, named for the genetic signaling pathways thought to play prominent roles in the development and progression of the cancer.
Their goal was to find the most abundantly expressed circular RNA in each group. In the case of SHH medulloblastoma, his team found only one, circ_63706, in higher amounts compared with the other three subtypes.
Next, they injected medulloblastoma intracranially into the cerebellum of circ_63706, knockout mice and mice with intact circ-63706 function to see how it impacted tumor growth. Mice without functioning circ_63706 had significantly smaller tumors than those transplanted with control cells.
Mice without functioning circ_63706 tumor cells were found to have reduced cell proliferation and significantly prolonged survival compared with the control group. “We saw a delay in the onset of tumor and reduction of the tumor itself suggesting that there is indeed a tumor suppressive effect of this circuitry,” adds Perera.
Exploring the mechanisms circ_63706 uses to promote cancer cell growth, Perera and colleagues uncovered a link to fatty acid lipid metabolism, which cancer cells use as a source of energy for tumor cell proliferation and growth.
They found when circ_63706 is turned off, fat metabolism increases, and this action, known as lipid oxidation, is toxic to cancer, ultimately leading to cell death. The researchers say these findings point to a potential for a targeted therapy, using a drug or drugs to block circ_63706 and cause tumor cells to die.
“If you look at the central dogma, RNA is translated to a protein and that’s the end-product,” says Perera, so therapeutic targeting usually focuses on protein. “Now we are working on the intermediate products —the RNA — to see if we destroy it, can we actually block it?” he adds.
Towards that end, he and his colleagues are pursuing several paths including identifying the factors guiding or driving circ-63706’s activity. One involves the upstream partners circ-63706 uses to exert its effects. “Maybe circular RNAs function not by themselves but with other molecules that bind to it,” Perera suggests. “If we can identify those partners, we can also modulate, block, or disrupt them and in so doing disrupt the activity of this circular RNA.” As a therapeutic strategy, the team is currently working with collaborators using coated nanoparticles with antisense oligonucleotides that target specific circular RNAs.
