Thusyanth is a biomedical sciences student at McMaster University. With his 2014 – 2015 research studentship, he will work with Dr. Sheila Singh at the Singh Laboratory at McMaster University – McMaster Stem Cell & Cancer Research Institute on a project focused on medulloblastoma brain tumours.
Generously funded in memory of Taite Boomer
About the Research
Project Title: Sox2 marks the treatment-refractory population on Shh-dependent medulloblastoma stem cells
Medulloblastoma (MB) is the most common type of malignant brain tumour in children, and is thought to arise from an abnormal stem cell. Recent research has categorized MB into four subgroups, of which one is characterized by activation of the Sonic hedgehog (Shh) signaling pathway. Research in the Singh Laboratory has identified Sox2, a gene used to mark normal neural stem cells as a unique downstream target in Shh-‐dependent MB. Consequently, the current project will further investigate the role of Sox2 in MB stem cells.
Of particular interest, Shh inhibitors have proven to be ineffecient in treating Group 2 MBs, and as a result, we will characterize the role of Sox2 in marking the treatment–refractory population in this particular subgroup of MB. We hope to discover the potential therapeutic role of Sox2 in controlling MB treatment response and to further develop the cancer stem cell hypothesis by linking genes and signalling pathways active in normal neural stem cells with those driving tumour formation and maintenance in MB.
About Thusyanth, in his own words…
Being awarded a Brain Tumour Research Studentship means an incredible opportunity given by the many supportive donors for young scientists such as myself to bring forth a positive impact in this intricate field of research. This prestigious award exemplifies the importance of giving it my all to overcome the barriers of becoming a successful researcher who can truly give back to his community.
My motivation to pursue a career in brain tumour research stems from my curiosity to learn about one of the most complex and critical diseases of our time and my desire to provide better outcomes for those affected by it. Though we have come a long way in advancing our knowledge in this area of research, we are still far from comprehending how to save lives from such diseases.
Within the two summer terms, I hope to attain valuable findings that can further improve our understanding of cancer development within the brain, which can aid us in our battle against brain tumours. As I eagerly wait to commence my research, I can see the benefits of this studentship, as it would not only influence my academic career but further encourages me to make a positive difference for our society.
Cancer remains to be the second leading cause of deaths in children, with central nervous system tumours classified as the leading cause of childhood cancer mortality. Moreover, medulloblastoma (MB), a pediatric intracranial tumour, is contemporarily noted to be the most frequent and malignant of all diagnosed brain tumours in childhood. Through recent improvements in cancer therapy treatments, standard risk MB patients were able to achieve an increased 5-year overall average survival rate of 90% as opposed to 50% previously. However, survivors now face the long-term toxic effects of current treatments that often lead to permanent neurological and developmental defects. Despite the state of the art combinatorial treatment methods from surgical resection to radiation therapy and chemotherapy, patients often experience tumour recurrence and tumour metastasis at primary sites. Inter-tumoural heterogeneity is a cardinal factor for the inefficiency of current chemotherapies targeting multiple cancer pathways. Currently, MB is classified into four subgroups based on severity, age of diagnosis, and metastatic potential: WNT signalling pathway dependent, Sonic Hedgehog (Shh) pathway dependent, Group 3, and Group 4.
The Shh dependent MB is one of the most researched subgroup, as its significance in normal cerebellar development hints at the involvement of stem-like cancer cells. According to the cancer stem cell (CSC) hypothesis, a rare population within a heterogeneous cancer noted as CSCs demonstrates stem cell properties such as self-renewal and multilineage differentiation. Brain tumour stem cells (BTSCs) identified by a neural stem cell marker CD133 or CD15 make up the subpopulation that can initiate and maintain a primary brain tumour. According to the CSC hypothesis, the BTSCs are not targeted by the standard treatment regime; therefore they repopulate and reformulate a secondary tumour. Patient relapse arising from tumour recurrence is what contributes to a poorer survival outcome, as additional surgical resection are deemed inefficient in children due to risks of neurological defects, severe toxic side effects and even death.
We discovered that patients exhibiting poorer clinical outcome such as treatment-resistant Shh-dependent MB actually maintain higher Sox2 expression levels. Sox2, a transcription factor required for normal brain development, has been further characterized as a pluripotent and neural stem cell marker that can now be used as a target for Shh-dependent MBs. However, to date we do not have congruent research that describes how Sox2 directly interacts with the agonists of the Shh pathway leading to the treatment refractory population of BTSCs in MBs.