Kasfa Mahi
English Writing for the Sciences 21003
Professor Katelyn Conroy
March 18, 2021
Abstract
Wnt, Shh, Group 3, and Group 4 are the four molecular subgroups that make up medulloblastoma (MB). The WNT subgroup of medulloblastoma tumors is the least common but has the best prognosis. Children and, to a lesser extent, adults are most commonly affected. They usually start in the area around the Luschka foramen and the middle cerebellar peduncle. Significant advancements in neurosurgery, radiotherapy, and chemotherapy have resulted in increased survival and cure rates for children with brain tumors in recent decades.1 Other potentially significant biological anomalies in pediatric medulloblastomas have been discovered thanks to newly developed array-based techniques for analyzing gene expression, protein expression, copy number aberrations, and epigenetic events. Information about the cells that cause brain tumors and the possibility of brain tumor stem cells has become available. More knowledge about the genetic and biological characteristics of these tumors is being gathered, which could help patients have a better outcome.
1 Karajannis, M., Allen, J., & Newcomb, E. (2008, December). Treatment of pediatric brain tumors. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574972/
Introduction
The most common malignant pediatric brain tumor, medulloblastoma (MB), is divided into four molecular subgroups: Wnt (Group 1), Shh (Group 2), Group 3, and Group 4. SHH or sonic hedgehog tumors are malignant tumors of the central nervous system. They are the second most common medulloblastoma subgroup (after group 4) and have a similar prevalence to group three. Group 3 and 4 tumors are malignant central nervous system tumors that are among the most common in children. They usually emerge from the cerebellum’s vermis and appear in childhood and infancy. In all the medulloblastoma subgroups, Group 3 has the worst prognosis. And WNT is a wingless subgroup of medulloblastoma tumors which seems to be uncommon. According to the research found, there can be three possible positive ways to help children have a better reaction to treatment. Chemotherapy was initially used as an adjuvant (applied after initial treatment for cancer, especially to suppress secondary tumor formation) treatment after surgery and radiation therapy, which resulted in substantial increases in progression-free and overall survival for many patients with malignant CNS (central nervous system) tumors like medulloblastoma. Another would be the biological parameters of medulloblastoma of pediatric brain tumors could lead to new insights into pathogenesis, easier diagnosis, improved risk-group stratification for treatment, or the discovery of new therapeutic targets. Lastly, WNT activation, and although the WNT, a wingless subgroup of medulloblastoma tumors, is rare, it has the best prognosis. A small molecule compound discovered in Dr. Sheila Singh’s lab at McMaster University and published today in the journal Nature Communications will stimulate the Wnt pathway in non-Wnt subtypes of medulloblastoma, making these aggressive cancers more receptive to therapies. Medulloblastoma is the most common form of pediatric brain tumor, accounting for 20% of all cases. I have analyzed three articles : “Treatment of Pediatric Brain Tumors” by Matthias Karajannis, Jeffrey C. Allen, and Elizabeth W. Newcomb published in 2009, “Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective” by Judith M. de Bont, Roger J. Packer, Erna M. Michiels, Monique L. den Boer, and Rob Pieters published in 2008, and “Wnt activation as a therapeutic strategy in medulloblastoma” by Branavan Manoranjan and other colleagues published in 2020, to answer my question of what treatments for prepubescent brain cancer such as Medulloblastoma are successful and how can they be made more successful?
How chemotherapy is helping children react better to brain cancer?
Significant advancements in neurosurgery, radiotherapy, and chemotherapy have resulted in increased survival and cure rates for children with brain tumors in recent decades. Brain tumors can be malignant which is cancerous or it may be benign which is not cancerous. The article “Treatment of Pediatric Brain Tumors” discusses proper clinical trial design and can be useful in evaluating current and innovative treatment methods for pediatric brain tumors such as low-grade and high-grade astrocytomas, medulloblastomas and ependymomas. However, we will be focusing more on medulloblastomas, improved survival and cure rates. Patients with medulloblastoma are currently divided into two groups: low-risk and high-risk.2 Patients who are under the age of three or who have a residual tumor mass following surgery of more than 1.5 cm2 or who have metastatic disease at the time of diagnosis are considered high-risk. The article states “Multi-agent chemotherapy has allowed the use of lower-dose craniospinal radiotherapy (CSRT) of 24 Gy with enhanced cure rates, as evidenced by a >80% event-free survival rate in standard-risk patients.” (Karajannis et al). This quote holds a great deal of positive information explaining the high risk patients circumstances of any residue tumor found after surgery or at diagnosis being removed with the help of chemotherapy instead of craniospinal radiotherapy which are seemingly very harsh on younger kids. The volumes and doses of radiotherapy needed for disease control cause serious brain damage in patients of all ages, most of which manifest as long-term neurocognitive sequelae, but they are particularly harmful to children under the age of six.3 As a result, most clinical methods have focused on halting or removing radiotherapy with the use of more severe chemotherapeutic approaches that have included potentially neurotoxic drugs including methotrexate or high-dose chemotherapy accompanied by autologous peripheral stem cell rescue.3 The article on WNT activation states “Previous work hypothesized the improved outcome in Wnt MB to be due to the secretion of soluble Wnt antagonists by tumor cells that may impair the blood–brain barrier, rendering it more susceptible to chemotherapy” (Manoranjan et al, 2020). The quote shows by the use of WNT signaling pathways it weakens the blood- brain barrier making the cancer more vulnerable to chemotherapy. Treatment for children with medulloblastoma remains a challenge however, chemotherapy has a positive reaction to slowly helping younger kids react to it better.
2 Karajannis, M., Allen, J., & Newcomb, E. (2008, December). Treatment of pediatric brain tumors. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574972/
How can taking biological parameters help doctors find better ways to treat medulloblastoma on children?
The article “Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective” is about pediatric brain tumor patients’ survival rates improving dramatically in recent years due to advances in neurosurgery, chemotherapy, radiotherapy, and supportive treatment. However, brain tumors remain a leading cause of cancer-related deaths in children. Prognosis is still heavily influenced by clinical factors such as the patient’s age, tumor type, stage, and location. “Medulloblastoma is the most common embryonal CNS tumor of childhood and is likely composed of biologically different subsets of tumors arising from stem and/or progenitor cells of the cerebellum.” (Bont et al, 2008). Pediatric brain tumors are caused by a variety of factors that are mostly unknown. Environmental factors such as smoking, diet, and other exposures have little effect on the development of tumors in the brain. Hereditary gene mutations, irradiation, and immune suppression account for just a small percentage of brain tumors. In 18-25 percent of medulloblastomas, immunohistochemistry has been shown to detect nuclear accumulation of β-catenin (Beta catenin is an important effector in signaling to the nucleus, where it stimulates transcription of Wnt-specific genes that control cell fate decisions in a variety of cells and tissues), and the existence of this biomarker suggesting activation of the Wnt signaling pathway predicts a favorable outcome.4 The biological knowledge for the diagnosis comes from blood, urine, and cerebrospinal fluid. Biomarkers are used as an indication of a biological factor that describes a subclinical manifestation, stage of the condition, or surrogate manifestation of the disease in these cases. The article by Manoranjan does not rely on any information regarding any biological parameters or factors however, they are looking more into the biological marks on WNT activation pathways and MB models. Additional information on the biological characteristics of pediatric brain tumors may lead to new insights into pathogenesis, make diagnosis easier, improve risk-group stratification for treatment, or lead to the development of new therapeutic targets. Many strategies have been established over the years to classify these biological factors. Newly discovered abnormally expressed genes and proteins, chromosomal alterations, DNA copy number defects, and other genetic changes, that may play a role in the pathogenesis and biological activity of the pediatric brain tumor subtype medulloblastomas. So, the use of biological factors can help researchers and doctors get a better understanding of medulloblastomas all inclusive to come up with a certain prognosis, however, more research is needed for certain cancers.
3De Bont, J., Packer, R., Michiels, E., Den Boer, M., & Pieters, R. (2008, December). Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719002/
4 Karajannis, M., Allen, J., & Newcomb, E. (2008, December). Treatment of pediatric brain tumors. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574972/
How does WNT activation help children with medulloblastoma?
The most common victims of medulloblastomas are children and, to a lesser degree, adults. The article “Wnt activation as a therapeutic strategy in medulloblastoma” is about the new finding of WNT activation which helps and attacks other types of medulloblastomas and decreases the original size. “Our work shows the Wnt pathway, which has historically been considered cancer-promoting, may function as a tumour suppressor in certain contexts….We also found all different subtypes do have a minority fraction of Wnt active cells, and this is promising.” (Manoranjan et al, 2020). Manoranjan discovered that a small percentage of cells in Group 2, 3, and 4 cancers were Wnt active, and that when those cells were sorted, they produced smaller, more benign-looking tumors, while Wnt inactive cells generated violent, metastatic tumors. The researchers then tested a small molecule that activated the Wnt pathway in mice with non-Wnt medulloblastoma tumors, finding that it reduced tumor growth and improved survival. Reduced beta catenin degradation occurs when the Wnt pathway is activated, followed by interactions with TCF/LEF (hundreds of genes are modulated by the TCF/LEF) transcription factors and activation of Wnt targets.3 In a significant number of medulloblastomas, activating mutations in the Wnt pathway are found. Furthermore, medulloblastomas from PTCH1 (Patched 1 is a patched gene family protein that is encoded by the gene) +/- mice have higher expression of genes involved in Wnt signaling activation.5 “The Wnt pathway is activated in 10% of sporadic medulloblastomas through mutations in β-catenin that activate Wnt signaling by removing critical inhibitory phosphorylation sites” (Karajannis et al, 2009). Phosphorylation is a primary determinant for changing the behavior of proteins after they’ve been formed and Beta catenin activates transcription of Wnt-specific genes that regulate cell fate decisions in a variety of cells and tissues. So the use of WNT signaling has proven to show a decrease and change behavior of the cancer cells.
5 De Bont, J., Packer, R., Michiels, E., Den Boer, M., & Pieters, R. (2008, December). Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719002/
Conclusion
Regarding the biological background in recent years, much progress has been made in identifying biological factors involved in the pathogenesis of pediatric medulloblastomas and ependymomas, but there is still much to learn. Although survival and cure rates have increased, treatment-related morbidity is still high, with severe long-term consequences. Our understanding of pediatric brain tumor biology bodes well for the development of new “molecular targeted” drugs that could complement, substitute, or even replace traditional chemotherapy and radiotherapy. To assess the safety and efficacy of these new methods, rigorous and well-designed clinical trials will be needed. Lastly, the WNT activation, the research and experiment have been well rounded and resulted in presenting an innovative targeted therapeutic strategy for treatment-resistant medulloblastoma.
BIBLIOGRAPHY
- De Bont, J., Packer, R., Michiels, E., Den Boer, M., & Pieters, R. (2008, December). Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719002/
- Karajannis, M., Allen, J., & Newcomb, E. (2008, December). Treatment of pediatric brain tumors. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574972/
- Manoranjan, B., Venugopal, C., Bakhshinyan, D., Adile, A., Richards, L., Kameda-Smith, M., . . . Singh, S. (2020, August 28). Wnt activation as a therapeutic strategy in medulloblastoma. Retrieved March 19, 2021, from https://www.nature.com/articles/s41467-020-17953-4
