Exploring new targeted therapies for sonic hedgehog (SHH) medulloblastoma
| dc.contributor.author | Cheetham, Stephanie | |
| dc.contributor.examiningcommittee | Doble, Brad (Pediatrics and Child Health, Biochemistry and Medical Genetics) | |
| dc.contributor.examiningcommittee | Drögemöller, Britt (Biochemistry and Medical Genetics) | |
| dc.contributor.supervisor | Werbowetski-Ogilvie, Tamra | |
| dc.date.accessioned | 2024-08-13T16:43:10Z | |
| dc.date.available | 2024-08-13T16:43:10Z | |
| dc.date.issued | 2024-08-02 | |
| dc.date.submitted | 2024-08-02T23:05:48Z | en_US |
| dc.degree.discipline | Biochemistry and Medical Genetics | |
| dc.degree.level | Master of Science (M.Sc.) | |
| dc.description.abstract | Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. MB is split into four molecular subgroups, with each subgroup displaying different gene expression profiles, genomic alterations, and responses to treatment. One subgroup is referred to as Sonic Hedgehog (SHH) MB and is defined by activation of the SHH signaling pathway. The current standard of care for MB consists of surgery, cytotoxic chemotherapy, and radiation to the entire brain and spinal cord. In spite of improved clinical outcomes, up to 40% of patients succumb to their disease while survivors are left with pervasive physical and cognitive delays as a result of the aggressive treatment. SHH MB exhibits extensive intratumoral heterogeneity which accounts for the bulk of treatment failures. Few personalized therapies for SHH MB exist, as SHH pathway antagonists are predicted to be ineffective in younger patients with tumors harbouring mutations in downstream SHH pathway genes. Novel, targeted therapies that have the possibility to reduce toxicity and improve survival are needed. The Ogilvie lab identified CD271, a neurotrophin receptor found exclusively in SHH MB. CD271 is diagnostic and prognostic in SHH MB, providing a highly specific therapeutic target. A small molecule named NSC49652 was found to bind to CD271. Binding of NSC49652 to CD271 leads to conformational changes in the receptor, leading to apoptosis by activating c-Jun N-terminal kinases. I hypothesized that NSC49652 would reduce SHH MB tumorigenic properties in vitro and would increase the length of survival and decrease tumor volume in vivo. My studies reveal that NSC49652 significantly reduces tumorigenic properties in vitro. In two SHH MB cell lines, NSC49652 resulted in decreases in tumorsphere size, tumorsphere number, cell migration, and cell viability. NSC49652 induces a decrease in tumorsphere number, which indicates decreased self-renewal capacity of the cancer stem cells (CSCs) that give rise to new tumorspheres. NSC49652 also decreases tumor volume and increases survival in an in vivo model of SHH MB. My work reveals a novel role for NSC49652 and warrants further investigation for the use of NSC49652 as a potential combination therapy for SHH MB. | |
| dc.description.note | October 2024 | |
| dc.description.sponsorship | Rady Faculty of Health Sciences Graduate Studentship Award | |
| dc.identifier.uri | http://hdl.handle.net/1993/38379 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | SHH medulloblastoma | |
| dc.subject | NSC49652 | |
| dc.subject | xenografts | |
| dc.subject | tumorspheres | |
| dc.subject | intratumoral heterogeneity | |
| dc.title | Exploring new targeted therapies for sonic hedgehog (SHH) medulloblastoma | |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no | |
| oaire.awardTitle | Research Manitoba Masters Studentship Award | |
| project.funder.name | Research Manitoba |