Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Out of the four molecular subgroups (WNT, SHH, Group 3 and Group 4), Group 3 patients face the highest incidence of leptomeningeal spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors, provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumors. The paucity of patient matched primary and recurrent MB samples has contributed to the lack of molecular targets specific to medulloblastoma recurrence, limiting relapsing MB patients to palliation. Our previous in silico analyses revealed enriched expression of many stem cell self-renewal regulatory genes in Group 3 MB.
In this work, I have set out to investigate whether by identifying genes contributing to self-renewal of Group 3 MB cells, we can characterize a population of cells responsible for therapy evasion and subsequent tumor relapse. Initially, we have adapted the existing COG (Children’s Oncology Group) protocol for children with newly diagnosed high-risk MB for treatment of immuno-deficient mice intracranially xenografted with human MB cells. Cell populations recovered separately from brains and spines mice during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. Additionally, we have investigated therapeutic potential of small molecules targeting BMI1, a known self-renewal regulating gene. In the setting of recurrent Group 3 MB, pharmacological inhibition of BMI1, led to a remarkable decrease in cell proliferation and self-renewal in vitro as well as reduction of local and spinal metastatic disease in vivo. Finally, by combining the established therapy-adapted patient-derived xenograft mouse model and BMI1 inhibitor, PTC-596, we have demonstrated an additive effect of two modalities and provided the pre-clinical data for the upcoming Phase I trial.
Biological investigations into the drivers of MB recurrence will lead to development of new therapeutic options for children who are frequently limited to palliation. Clinically relevant mouse models of MB recurrence can serve as platforms for pre-clinical testing and validation of new treatments aimed to provide therapeutic intervention rather than palliation. / Thesis / Doctor of Philosophy (PhD) / Medulloblastoma is the most common type of brain cancer that affects children. Out of the four main subgroups of medulloblastoma, tumors in Groups 3 and 4 are the most aggressive and are associated with a low overall survival in children diagnosed with this type of brain cancer. These two subtypes of medulloblastoma also account for the largest number of patients in which gold standard therapies fail and no additional therapies are available. Several studies have shown the existence of few cells within the tumor that alone can drive tumor growth. The aggressive behavior of these cells has in part been attributed to dysregulation of genes involved in cell replication and division. Further studies that will focus on understanding the significance of genes that regulate cell growth and replication can help discover a population of cells that is capable of evading therapy and contribute to tumor relapse. The identification and characterization of such population can lead to development of novel treatments for the children affected with aggressive medulloblastoma. In my thesis, I have developed a mouse model that replicates the aggressive therapy given to the medulloblastoma patients in order to study cells capable of escaping the harsh treatment and drive tumor comeback. Next, by profiling the gene expression and functional attributes of those cells, we identified genes that contribute to regulation of cell division and growth. The effects of both increasing and decreasing the activity of those genes were then tested in cells grown in the dish. Subsequently, the most promising results were verified in the established mouse models. The main objective of my thesis was to discover new opportunities in treatments the most aggressive type of brain cancer affecting children, and thus not only improve the quality of treatment but also the overall survival of patients with medulloblastoma.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25191 |
| Date | January 2019 |
| Creators | Bakhshinyan, David |
| Contributors | Singh, Sheila, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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