It may soon be possible to identify group 4 medulloblastomas from more aggressive group 3 tumors. Research based on a little-explored part of RNA that creates proteins may lead to the development of better-targeted therapies, according to investigators at the Johns Hopkins Kimmel Cancer Center. Findings from the study were published by Lee et al in Neuro-Oncology Advances.
Four groups of medulloblastomas have been identified, group 3 being the most aggressive. Group 4 is the most common type of medulloblastoma, accounting for 35% to 40% of all cases. To date, it has been difficult to distinguish group 3 tumors from group 4 tumors. Treatment for group 3 tumors is more aggressive than therapy for group 4 tumors, and it often includes radiation therapy. Distinguishing between group 3 and group 4 medulloblastomas currently relies on immunohistochemistry of tissue samples and imaging.
“Group 3 and group 4 medulloblastomas are very similar to each other, and it’s hard to differentiate them under the microscope. So, we started looking at the molecular markers,” said senior study author Ranjan J. Perera, PhD, Associate Professor of Oncology at the Johns Hopkins University School of Medicine, Director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital (JHACH), and a senior scientist at the JHACH Cancer & Blood Disorders Institute.
Role of SPRIGHTLY
In particular, the investigators looked at long noncoding RNAs (lncRNAs), which experts thought did not play a role in building proteins. New evidence, however, finds that they may play a role in regulating gene expression that impacts cancer growth and behavior.
Dr. Perera and co-investigators found that a lncRNA gene, called SPRIGHTLY, is highly expressed in group 4 medulloblastomas, but not group 3 tumors. “We found that this lncRNA (SPRIGHTLY) interacts with one gene called SMYD3,” Dr. Perera said. SMYD3 regulates EGFR, which helps the cancer develop new blood vessels that nourish the tumor. “Clearly, SPRIGHTLY could serve as a biomarker for group 4, because we have not seen this in group 3 or the other two groups,” he added.
The researchers studied SPRIGHTLY in mouse and human models of medulloblastomas and observed that without SPRIGHTLY, developing tumors were smaller than cells. Tumor growth was also slower in models where SPRIGHTLY was deactivated, supporting the role of SPRIGHTLY in tumor growth and proliferation.
In addition, the investigators conducted laboratory tests that showed that SPRIGHTLY interacts with another protein called PTPB1, which regulates SMYD3 protein production. This pathway enhances the expression of EGFR in group 4 medulloblastomas—and potentially provides a treatment target. There are several existing drugs that inhibit EGFR. Future work is needed to better understand the molecular mechanisms of the SPRIGHTLY pathway in group 4 medulloblastomas before investigation of treatments.
The study authors concluded: “These results demonstrate the importance of SPRIGHTLY lncRNA as a promoter of group 4 medulloblastoma and the role of the SPRIGHTLY-SMYD3-PTPB1 axis as an important oncogenic regulator in medulloblastoma.”
Disclosure: The work in this study was supported in part by the Schamroth Project funded by Ian’s Friends Foundation, Hough Family Foundation, and Susan and Robb Hough to Ranjan J. Perera and George Jallo; and an NCI grant to Ranjan J. Perera and Charles Eberhart. The technology is available for licensing through Johns Hopkins Technology Ventures. For full disclosures of the study authors, visit academic.oup.com.
