Basic Science Research
Molecular Profiling of Aggressive Meningiomas.
Meningiomas are the most common primary brain tumor, but are severely understudied. Although most patients can be cured with surgery alone, some patients exhibit relentless recurrence of disease despite multiple rounds of surgical and radiation therapies. We are learning that these aggressive meningiomas have a different biology than those that are cured with surgery alone. Using state-of-the-art genetic sequencing techniques, we are studying the biology of meningiomas in order to better define those tumors that are aggressive with hopes of finding new medical treatment options that are in dire need for these patients. Our lab is amongst the first to identify a methylation signature in meningiomas that can more accurately predict risk of recurrence than the standard classifications that routinely used in clinical care. For more information on this please visit our Methylation Program page.
Metabolism of Gliomas.
Gliomas are the most deadly brain tumors. Recent genetic studies have demonstrated that most gliomas harbour a mutation in the isocitrate dehydrogenase (IDH) gene. This mutation results in accumulation of the 2-hydroxyglutarate metabolite which facilitates tumor growth and invasion. It is clear that the metabolism of gliomas can be altered by this mutation. We are using High-performance liquid chromatography combined with mass spectrometry techniques in order to better understand the implications of altered metabolism in the context of other genetic changes in gliomas.
Molecular characterization of the full spectrum of peripheral nerve sheath tumors
Neurofibromatosis Type 1 (NF1) is a hereditary tumor predisposition syndrome that afflicts 1 in 3500 people and results in the development of innumerable peripheral nerve sheath tumours. These tumours fall within a spectrum of benign and malignant tumours. Although a large number of these tumours are benign, the cause significant morbidity such as intractable pain, physical disfigurement and neurological deficits. In addition, a subset of these tumours have a risk of malignant transformation into a high grade sarcoma called malignant peripheral nerve sheath tumours (MPNSTs); however, the mechanism of malignant transformation is poorly understood. We will leverage a multi platform integrated molecular analysis of the full spectrum of peripheral nerve sheath tumours to better understand the biology of oncogenesis and identify novel therapeutics as potential treatments.
Proteogenomics of Recurrent Gliolastoma Multiforme (GBM)
Our research focuses on better understanding the changes that occur to GBM between initial diagnosis and recurrence. Currently, these tumours inevitably recur and there is no standard treatment for recurrent disease. We will be utilizing a multi-omics approach to identify new biomarkers and better understand recurrent GBM. This will allow us to better predict response to treatment, recurrence, and prognosis and identify novel therapeutic targets.
Application of Novel Machine Learning Approaches for Recurrence Risk Prediction in Meningioma Based on Methylome Analysis:
Our goal is to develop clinical machine-learning tool to predict early recurrence risk in each meningioma patient using DNA methylation signatures and prognostic clinical factors. The approaches for the predictor are based on (1) GBM (generalized boosting machine) classification model to calculate the probability of recurrence over a time cut-off, (2) continuous survival random-forest modelling to calculate the probabilities of a recurrence over various time frames, (3) Integrate two models (continuous time or cut off time based) to create a robust/improved classifier, and (4) finally choose important minimal signatures possible from the methylation data for different years of cut-off (expected features to be less than number of events / recurrence).
Survival Stratification of IDH Mutant Glioma Using Methylation and mRNA based Integrated Approach:
Diffuse Glioma is genomically separated into IDH mutant (IDHmut) and IDH wild type tumors which defines prognosis in gliomas. We aim to characterize IDHmut LGG multi-omic platforms and identify methylation signature of outcome, and validate them with external test set. Initial results showed that multiple platform based integrated approach provided a clinically and biologically relevant subtypes that showed a strong correlation with patient survival and somatic mutations.
Comprehensive Methylome Analysis of EGFR-mutant Primary Lung Adenocarcinoma and Matched Brain Metastasis:
Lung Adenocarcinomas (LUAD) are the most common lung tumours and EGFR-mutant LUAD have a higher risk of brain metastasis development, which leads to poorer survival. Genetic, epigenetic or mutational signatures of brain metastasis from LUAD have not been WELL characterized yet. In this project, we are interested in (1) comparing the EGFR-mutant primary LUAD to matched brain metastasis to understand mechanisms of brain metastasis, (2) comparing FIRST (initial) BM and recurrent BM pairs to identify genomic alterations.
Epigenomics of Brain Metastases and their Primary Tumours.
The metastasis of lung, breast, and melanoma cancer to a patient’s brain significantly worsens their prognosis. Unfortunately, there is no reliable method to determine which patients will develop brain metastases currently. We are identifying DNA methylation signatures that predict which patients will develop brain metastases from their primary lung, breast and melanoma cancers and are also characterizing DNA methylation differences between brain metastases and the corresponding primary tumours. This work may allow for the identification of new treatment targets to prevent brain metastases and for clinicians to match the extent of treatment to a patient’s risk of poor oncological outcomes. It may also improve our understanding of the mechanisms that allow for tumour spread to the brain.
Epigenomic Drivers of Chordoma Recurrence.
Chordomas represent 20% of primary spine and skull base tumours and survival remains poor despite standard treatment of surgery and post-operative radiotherapy. Patients that develop a recurrence of their chordoma experience poorer survival and unfortunately there is no robust approach to predict which patients will have a recurrence. We are identifying DNA modifications, including methylation signatures and histone marks, that predict which patients will experience chordoma recurrence. We are also screening drugs which target the epigenetic signatures that we are identifying. This work may provide clinicians with information allowing them to balance the extent of a patient’s treatment with their risk of having poor outcomes and it may also lead to the identification of new chordoma treatments.
Non-invasive Diagnosis of Central Nervous System Tumours.
Currently, after the diagnosis of an intra-axial brain tumour on imaging, surgery is required in order to provide a definitive diagnosis from a wide differential ranging from benign to malignant lesions before treatment is planned. Recent work has shown that DNA methylation alterations in central nervous system tumours can be utilized for diagnostic purposes. We are identifying DNA methylations alterations non-invasively, using cell-free tumour DNA found in patient blood, and exploiting these signatures to classify different brain tumour types. This work may lead to the diagnosis of brain tumours without the need for invasive tissue sampling and thereby allow for the coordination of appropriate patient treatment, including radiotherapy or targeted therapies, without surgery.
Investigating the role of macrophages in glioblastoma angiogenesis and treatment resistance.
Glioblastoma (GBM) is characterized by pathologically altered vessels that are tortuous, hyperdilated, and leaky. Tumour vascularization is highly dependent on the tumour microenvironment and our laboratory, among several others, have shown that bone marrow-derived macrophages are actively recruited to perivascular regions within the tumour where they are thought to provide a supportive role for blood vessels. However, the specific role of macrophages in GBM angiogenesis and underlying molecular mechanisms have not been well-characterized. Preliminary data from our lab has now shown that glioma-associated macrophages (GAMs) secrete TNF-alpha to upregulate genes involved in endothelial cell activation, a pro-inflammatory response that may drive aberrant tumour angiogenesis. The overall objective of this project is to further elucidate the molecular mechanisms and functional impact of GAMs on endothelial cells (EC) to gain a better understanding of their role in tumour angiogenesis and resistance to therapy.
Generation and characterization of a novel syngeneic GBM mouse model
We have previously generated a novel transgenic Glioblastoma Multiforme (GBM) mouse model that recapitulates the genetic mutations found in ‘classical’ subtype of human GBM. This mouse model, called GEC3, overexpresses EGFRvIII under the astrocyte-specific promoter, GFAP, in combination with heterozygous knockout of CDKN2A. These mice spontaneously acquire brain tumours around 2-5 months of age. However, for drug studies it is ideal to use a xenograft model where all tumours can be implanted at the same time and progress along the same time course so that treatment can be initiated at a specific time point to determine response to therapy. We have isolated and cultured glioma stem cells from GEC3 tumours, which we will now implant into GEC3 genotype negative mice to validate the tumourigenicity of these cells and generate a syngeneic mouse model that can be used for drug studies.