The Efficacy of Targeting Cell Cycle Regulators in the Treatment of Medulloblastoma
Type of Proposal
Oral presentation
Faculty
Faculty of Science
Faculty Sponsor
Dr. Lisa A. Porter
Proposal
Medulloblastoma (MB) is the most common malignant brain tumour diagnosed in children. This type of brain tumour is comprised of four molecular subgroups: WNT, Sonic Hedgehog (SHH), Group 3, and Group 4. Previous research has indicated that these four subgroups have a diverse set of clinical features, genetics, and cell subpopulations driving the tumour progression and resistance to treatment. Currently, a combination of surgery, radiotherapy, and chemotherapy are used to treat MB. Standard of care chemotherapy is a very aggressive protocol characterized by high general cytotoxicity. The search for new drugs efficiently targeting MB at the source of its origin, both on the genetic as well as cellular level is of high importance. In our lab, we study a cell cycle regulatory protein called Speedy (Spy1) which is able to override select cell cycle checkpoints thereby providing an avenue for cells to over-proliferate and become cancerous. Speedy is implicated in the maintenance of the aggressive and expansive stem-like populations of tumour initiating cells in the most aggressive brain tumour known, glioblastoma multiforme. It is our hypothesis that Spy1 drives specific populations of tumour initiating cells in MB and the reduction of Spy1 levels will increase sensitivity to synthetic CKIs (cyclin-dependent kinase inhibitors). To address our hypothesis we have sorted select populations of patient-derived MB initiating cells and have manipulated levels of Spy1 and/or Cyclin E1 using a lentiviral system. We use a high throughput platform where manipulated human cancer cells are injected into Zebrafish prior to establishment of the acquired immune system. This allows us to determine the effect of specific factors on tumour foci formation and cell characteristics in the presence of an intact immune system. We also study the effect of specific drugs on these in vivo tumours. This work addressed the role of Spy1 and other cyclins on MB aggressiveness and response CKI treatment. The results from our study will not only aid in better understanding of MB biology and dissecting its molecular drivers, but will potentially contribute to improved design of therapy regimens and successful clinical outcome.
Start Date
29-3-2016 4:00 PM
End Date
29-3-2016 5:00 PM
The Efficacy of Targeting Cell Cycle Regulators in the Treatment of Medulloblastoma
Medulloblastoma (MB) is the most common malignant brain tumour diagnosed in children. This type of brain tumour is comprised of four molecular subgroups: WNT, Sonic Hedgehog (SHH), Group 3, and Group 4. Previous research has indicated that these four subgroups have a diverse set of clinical features, genetics, and cell subpopulations driving the tumour progression and resistance to treatment. Currently, a combination of surgery, radiotherapy, and chemotherapy are used to treat MB. Standard of care chemotherapy is a very aggressive protocol characterized by high general cytotoxicity. The search for new drugs efficiently targeting MB at the source of its origin, both on the genetic as well as cellular level is of high importance. In our lab, we study a cell cycle regulatory protein called Speedy (Spy1) which is able to override select cell cycle checkpoints thereby providing an avenue for cells to over-proliferate and become cancerous. Speedy is implicated in the maintenance of the aggressive and expansive stem-like populations of tumour initiating cells in the most aggressive brain tumour known, glioblastoma multiforme. It is our hypothesis that Spy1 drives specific populations of tumour initiating cells in MB and the reduction of Spy1 levels will increase sensitivity to synthetic CKIs (cyclin-dependent kinase inhibitors). To address our hypothesis we have sorted select populations of patient-derived MB initiating cells and have manipulated levels of Spy1 and/or Cyclin E1 using a lentiviral system. We use a high throughput platform where manipulated human cancer cells are injected into Zebrafish prior to establishment of the acquired immune system. This allows us to determine the effect of specific factors on tumour foci formation and cell characteristics in the presence of an intact immune system. We also study the effect of specific drugs on these in vivo tumours. This work addressed the role of Spy1 and other cyclins on MB aggressiveness and response CKI treatment. The results from our study will not only aid in better understanding of MB biology and dissecting its molecular drivers, but will potentially contribute to improved design of therapy regimens and successful clinical outcome.