image: Rajan Perera, Ph.D. view more
Credit: Allyn DiVito
It may soon be possible to identify Group 4 medulloblastomas—the most common malignant brain tumor in children--from more aggressive Group 3 tumors. Research based on a little-explored part of RNA, which creates proteins, could lead to the development of better-targeted cancer treating drugs, according to investigators at the Johns Hopkins Kimmel Cancer Center.
Four groups of medulloblastomas have been identified, with Group 3 being the most aggressive — survival at 5 years is a 45% to 60% rate. Group 4 is the most common form of medulloblastoma, accounting for 35-40% of all cases.
The findings were published in Aug. 22 in the journal Neuro-Oncology Advances.
To date, it is difficult to distinguish Group 3 tumors — which have a better prognosis (five-year survival is 75%-80%) — from Group 4 tumors. Treatment for Group 3 is more aggressive than Group 4, often including radiation therapy. Distinguishing between Group 3 and Group 4 medulloblastomas relies on immunohistochemistry of tissue samples--specialized testing used to distinguish types—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 Perera, Ph.D., director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital (JHACH) in St. Petersburg, Florida. Perera is also a senior scientist at the JHACH Cancer & Blood Disorders Institute and an associate professor of oncology at the Johns Hopkins University School of Medicine. He has a secondary affiliation with the JHACH Institute for Fundamental Biomedical Research.
In particular, the investigators looked at long non-coding RNA (lncRNA), which experts thought did not play a role in building proteins. New evidence, however, finds that they play a role in regulating gene expression that impacts cancer growth and behavior.
Perera and coinvestigators found that a lncRNA gene, called SPRIGHTLY, is highly expressed in Group 4 medulloblastomas, but not Group 3. “We found that this long noncoding RNA (SPRIGHTLY) interacts with one gene called SMYD3,” he said. SMYD3 regulates endothelial growth factor receptor (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 says.
The researchers studied SPRIGHTLY in mouse and human models of medulloblastoma and observed that developing tumors were smaller than cells without SPRIGHTLY. Tumor growth was also slower in models where SPRIGHTLY deactivated, supporting the role of SPRIGHTLY in tumor growth and proliferation.
The investigators also 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. Of course, much work is needed to better understand the molecular mechanisms of the SPRIGHTLY pathway in Group 4 medulloblastomas before investigation of treatments.
In addition to Perera, study co-authors were Bongyong Lee, Keisuke Katsushima, Rudramani Pokhrel, Menglang Yuan, Stacie Stapleton, George Jallo and Charles Eberhart of Johns Hopkins; Robert J. Wechsler-Reya of Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California; and Animesh Ray of Keck Graduate Institute in Claremont, California, and California Institute of Technology in Pasadena, California.
The work 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 NCI grant to Ranjan J. Perera and Charles Eberhart (1R37CA230400).
Journal
Neuro-Oncology Advances