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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 tumorsp

Rare diseases (RDs) affect 2.5 million Canadians, often starting in childhood. Due to medical complexities and limited disease knowledge, many children with RDs are known to face a lengthy diagnostic odyssey. Previous research highlights the need for social connection to other RD families, informational resources, and psychosocial support among parents and caregivers of children with RDs. Our study aims to fill a knowledge gap by examining Canadian RD caregivers’ experiences, preferences, and informational and support-seeking behaviours of Canadian RD caregivers, and how these outcomes and are correlated with various demographic factors. We analyzed a total of 95 eligible survey responses from eligible Canadian caregivers. Over half of caregivers received a diagnosis for their child within the first year of medical investigations, and a similar proportion believed the diagnosis could have been made earlier. Overall, caregivers had positive perceptions of their interactions with their child’s genetics healthcare provider (gHCPs). These perceptions were significantly associated with caregiver income, education, and type of condition that was diagnosed. Caregivers primarily relied on internet webpages, support groups, and personal networks for informational and emotional support. However, these preferences varied based on a variety of demographic factors. Notably, caregivers’ perceived level of emotional support did not improve after obtaining a diagnosis for their child, and a minority of caregivers were offered counselling, emotional support, or recommendations of support groups/RD organizations. This study quantitatively examines Canadian RD caregivers’ experiences, including their diagnostic journey, interactions with gHCPs, and their informational and support seeking behaviours. Our findings suggest that caregivers require additional psychosocial support particularly at the time of their child’s diagnosis and in the period following obtaining their diagnosis. The

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 molecular subgroups that exhibit different genomic alterations, gene expression profiles and response to treatment. We have previously shown a novel role for the MEK/MAPK pathway in specifically contributing to Sonic Hedgehog (SHH) MB tumor progression. Here, we compared the effect of the MEK inhibitor (MEKi) selumetinib to the more potent MEKi trametinib on tumor cell properties in vitro and assessed the effect of trametinib in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduced tumorsphere size, stem/progenitor cell proliferation and viability at much lower concentrations than selumetinib. RNA sequencing corroborated these findings with significant decreases in cell cycle and stem cell pathways concomitant with increases in pathways associated with cell differentiation and ciliopathies following MEKi treatment. Importantly, trametinib also decreased tumor growth and increased survival in vivo and this was accompanied by similar decreases in cell cycle related pathways as well as increases in IL6/JAK STAT3 signaling. Our study reveals a novel role for trametinib in effectively attenuating MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB.

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 molecular subgroups that exhibit different genomic alterations, gene expression profiles and response to treatment. We have previously shown a novel role for the MEK/MAPK pathway in specifically contributing to Sonic Hedgehog (SHH) MB tumor progression. Here, we compared the effect of the MEK inhibitor (MEKi) selumetinib to the more potent MEKi trametinib on tumor cell properties in vitro and assessed the effect of trametinib in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduced tumorsphere size, stem/progenitor cell proliferation and viability at much lower concentrations than selumetinib. RNA sequencing corroborated these findings with significant decreases in cell cycle and stem cell pathways concomitant with increases in pathways associated with cell differentiation and ciliopathies following MEKi treatment. Importantly, trametinib also decreased tumor growth and increased survival in vivo and this was accompanied by similar decreases in cell cycle related pathways as well as increases in IL6/JAK STAT3 signaling. Our study reveals a novel role for trametinib in effectively attenuating MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB.