Education & Certifications
Master of Science, University of Toronto, Neuro-Oncology (2018)
Honors Bachelor of Science, University of Toronto, Neuroscience and Molecular Biology (2015)
Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.
View details for DOI 10.1038/s41467-018-08087-9
View details for PubMedID 30737375
View details for PubMedCentralID PMC6368580
Pituitary apoplexy is associated with visual, cranial nerve, and endocrine dysfunction. In this article, the results of surgical and conservative management of pituitary apoplexy in a single center are evaluated and a review of the literature is presented.A retrospective analysis was made of patients with pituitary apoplexy who underwent surgery or conservative management at our center between January 2007 and June 2017. Surgery was typically selected for patients who presented with acute deterioration of visual status and/or level of consciousness. Patients with no visual field deficit and those who had medical contraindications to undergo a surgical procedure because of previous comorbidities typically had conservative treatment. Baseline characteristics and clinical and radiologic outcomes were reviewed. A review of the literature (1990-2018) was performed according to PRISMA guidelines. Studies comparing the results of conservative and surgical management were identified. Visual, cranial nerve, and endocrine outcomes and tumor recurrence were analyzed.Forty-nine patients (73.1%) were managed surgically and 18 (26.9%) conservatively. After careful case selection, patients underwent surgical or conservative treatment. Patients who underwent conservative treatment had fewer visual deficits. At diagnosis, visual deficit (38.8%†vs. 75.5%; P†= 0.008) and cranial nerve palsy (27.7%†vs. 51%; P†= 0.058) were less common in the conservative group. Conservative and surgical treatments had similar visual and cranial nerve improvement rates (75% vs. 58.3%, P†= 0.63 and 75% vs. 69.2%, P†= 1.0, respectively). In the conservative group, tumor shrinkage was observed in 76.4% of cases. The systematic review retrieved 11 studies. No significant difference between conservative and surgical treatment for clinical outcomes (visual field recovery, odds ratio [OR], 1.45; 95% confidence interval [CI], 0.72-2.92; cranial nerve recovery, OR, 2.30; 95% CI, 0.93-5.65; and hypopituitarism, OR, 1.05; 95% CI, 0.64-1.74) or tumor recurrence (OR, 0.68; 95% CI, 0.20-2.34) was observed.A tailored approach to pituitary apoplexy, one that does not include an absolute need for surgery, is appropriate. Conservative management is appropriate in selected patients presenting without visual deficits.
View details for DOI 10.1016/j.wneu.2019.07.055
View details for PubMedID 31302273
Isocitrate dehydrogenase (IDH) mutations are common in low grade gliomas and the IDH mutation status is now integrated into the WHO classification of gliomas. IDH mutations lead to preferential accumulation of the R- relative to the S- enantiomer of 2-hydroxyglutarate (2-HG). We investigated the utility of tissue total 2-HG, R-2-HG and the R-2-HG/S-2-HG ratio (rRS) as diagnostic and prognostic biomarkers for IDH mutations in gliomas.Glioma tissue and blood samples from 87 patients were analyzed with HPLC-MS/MS coupled with a CHIROBIOTIC“ column to quantify both enantiomers of 2-HG. Receiver operator curve (ROC) analysis was conducted to evaluate the sensitivity and specificity of 2-HG, R-2-HG and rRS. The feasibility of real-time determination of IDH status was evaluated in 11 patients intra-operatively. The prognostic value of rRS was evaluated using the Kaplan-Meier method.The rRS in glioma tissues clearly distinguished patients with IDH mutant versus wildtype tumors (p<0.001). Sensitivity and specificity using an rRS cut-off value of 32.26 were 97% and 100% respectively. None of total 2-HG, R-2-HG or rRS was elevated in serum samples. Among patients with IDH mutant tumors, tissue rRS stratifies overall survival. The duration of tissue analysis is approximately 60 minutes.Our study demonstrates that rRS is a reliable biomarker of IDH mutation status. This technique can be used to determine IDH mutation status intra-operatively, and to guide treatment decisions based on IDH mutation status in real time. Lastly, rRS values may provide additional prognostic information and further validation is required.
View details for DOI 10.1158/1078-0432.CCR-18-3205
View details for PubMedID 30777876
HK2 is elevated in GBM and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient derived glioma stem cells, and mouse models of GBM.We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2 associated gene signature. We next determined the EC50 of the compounds by treating glioma cell lines and glioma stem cells. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on tumor cell metabolic activity was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, Ketoconazole and Posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo Treatment of mice bearing GBM with Ketoconazole and Posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. Additionally, treatment with azoles resulted in increased proportion of apoptotic cells.Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM., Combined with existing literature and pre-clinical results these data support the value of repurposing azoles in GBM clinical trials.
View details for DOI 10.1158/1078-0432.CCR-18-1854
View details for PubMedID 30322879
Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a†cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.
View details for DOI 10.1007/s00401-018-1821-3
View details for PubMedID 29428975
View details for PubMedCentralID PMC5978937
Important advances in our understanding of the molecular biology of brain tumors have resulted in a rapid evolution in the taxonomy of central nervous system (CNS) tumors, which culminated in the revised 2016 World Health Organization classification of CNS tumors that incorporates an integrated molecular/histologic diagnostic approach. Our expanding understanding of brain tumor genomics and molecular evolution during the disease course has started to impact clinical management. Furthermore, incorporation of genomic information in ongoing and planned neuro-oncology clinical trials is expected to lead to improved outcomes and result in personalized treatment options for patients with CNS malignancies.
View details for DOI 10.1200/EDBK_200989
View details for PubMedID 30231374
Molecular markers provide important biological and clinical information related to the classification of brain tumors, and the integration of relevant molecular parameters into brain tumor classification systems has been a widely discussed topic in neuro-oncology over the past decade. With recent advances in the development of clinically relevant molecular signatures and the 2016 World Health Organization (WHO) update, the views of the neuro-oncology community on such changes would be informative for implementing this process.A survey with 8 questions regarding molecular markers in tumor classification was sent to an email list of Society for Neuro-Oncology members and attendees of prior meetings (n=5065). There were 403 respondents. Analysis was performed using whole group response, based on self-reported subspecialty.The survey results show overall strong support for incorporating molecular knowledge into the classification and clinical management of brain tumors. Across all 7 subspecialty groups, ?70% of respondents agreed to this integration. Interestingly, some variability is seen among subspecialties, notably with lowest support from neuropathologists, which may reflect their roles in implementing such diagnostic technologies.Based on a survey provided to the neuro-oncology community, we report strong support for the integration of molecular markers into the WHO classification of brain tumors, as well as for using an integrated "layered" diagnostic format. While membership from each specialty showed support, there was variation by specialty in enthusiasm regarding proposed changes. The initial results of this survey influenced the deliberations underlying the 2016 WHO classification of tumors of the central nervous system.
View details for DOI 10.1093/neuonc/now181
View details for PubMedID 27688263
View details for PubMedCentralID PMC5464323
Tumors of the CNS are composed of a complex mixture of neoplastic cells, in addition to vascular, inflammatory and stromal components. Similar to most other tumors, brain tumors contain a heterogeneous population of cells that are found at different stages of differentiation. The cancer stem cell hypothesis suggests that all tumors are composed of subpopulation of cells with stem-like properties, which are capable of self-renewal, display resistance to therapy and lead to tumor recurrence. One of the most important transcription factors that regulate cancer stem cell properties is SOX2. In this review, we focus on SOX2 and the complex network of signaling molecules and transcription factors that regulate its expression and function in brain tumor initiating cells. We also highlight important findings in the literature about the role of SOX2 in glioblastoma and medulloblastoma, where it has been more extensively studied.
View details for DOI 10.2217/cns-2016-0001
View details for PubMedID 27230973
View details for PubMedCentralID PMC6042636
Chordoid meningioma (CM) is a rare subtype of meningioma, classified as grade II, which exhibits a high rate of recurrence following subtotal resection. We retrospectively examined nine cases of chordoid meningioma over a case series of 1743 meningiomas (0.52%) operated upon at our institution from 1995 to 2013. All the reported clinicopathological findings were analyzed. Two hundred and twenty-one CM cases have been published to date worldwide and few single-center large case series have been issued. Seventy-five percent of the cases that underwent subtotal resection at our institution had recurrence within 1 year. Total resection of the tumor should be the major objective of surgery to reduce the possibility of tumor recurrence. The percentage of chordoid features within the tumor specimen could assist in predicting the pathogenesis of the lesion. The correlation of the index of proliferation to recurrence rate is still controversial. Much debate exists with regard to the role of adjuvant radiotherapy in CM cases. Immunohistochemical, cytological and ultrastructural studies should be used in combination to assure a correct diagnosis of CM. Owing to the rare occurrence of this meningioma subtype, larger case series are required to assist in providing a reference for diagnosis and to improve the therapeutic management of CM.
View details for DOI 10.1111/neup.12174
View details for PubMedID 25378105