Our Research

Research highlights

Expansion of the Sydney Brain Tumour Bank to Chris O’Brien Lifehouse and WSLHD

Glioma is the most common and aggressive form of adult primary brain cancer and currently there is no cure. Capturing biospecimens and recording clinical information is crucial for research into better treatments and outcomes for patients. The Sydney Brain Tumour Bank was established in the RPA Department of Neuropathology and we recently expanded our activities to The Chris O’Brien Lifehouse and Westmead Public and Private hospitals. Brain tumour tissues removed in theatres from consented patients are now routinely snap frozen, and living tumour cells and bloods specimens are processed, preserved and stored at the NSW Statewide Biobank. We have launched a comprehensive brain cancer biospecimen and clinical data registry which brings together biospecimens and data collected at all Sydney Brain Tumour Bank sites.

Along with our prospective collections, we are working to clinically annotate more than 1000 archived brain tumour biospecimens, including material captured from approximately 300 glioma patients. New research platforms are being developed from this archive, including tissue microarrays and next generation sequencing panels, which will be available for collaborative glioblastoma and glioma research studies.

GlioNET Observational Study

Principal Investigators: Dr Kimberley (Kaufman) Alexander, A/Prof Michael Buckland, Dr Brindha Shivalingam, Dr Hao-Wen Sim

The GlioNET Study is the first concerted effort to track and observe glioma patients over the entire course of their cancer journey. This prospective study is “observational” and records complete clinical and pathological information, imaging and survival data, and collects biospecimens (tumour tissues, living cells and blood samples) at multiple time points. GlioNET also surveys patients about their quality of life, quality of sleep and other symptoms during and after treatments. GlioNET participants also have access to a daily symptom tracking smartphone App, ‘OurBrainBank’. OurBrainBank is an International, patient-led movement designed to move glioblastoma from terminal to treatable. The App is used to track symptoms, instantly share information with treating clinicians, and donate data to medical research studies, including GlioNET.

All materials and information captured by GlioNET will create a unique, open-access platform critical glioma and glioblastoma research. The GlioNET bioresource is designed to support several research studies under four key aims:

AIM 1. Innovate and deliver next-generation diagnostics for glioma
AIM 2. Fundamental research to understand how glioma tumours grow, spread and resist treatments
AIM 3. Discover novel treatments for glioma
AIM 4. Identify opportunities for improving services and quality of life for patients and caregivers

The GlioNET project pilot was launched at the Chris O’Brien Lifehouse and RPA Hospital in early 2020. We now have 30 participants enrolled and have preserved tumour material from 34 neurosurgeries, plasma and serum from 121 blood collections, captured 84 completed surveys along with comprehensive clinical, pathological and radiological data. While this collection strategy is showing early promise, the relatively low incidence rate of glioma means that a coordinated effort is crucial to capture a patient population sufficiently large enough for high-quality, statistically significant scientific research. It is our goal to expand the GlioNET study from a local initiative to one that is Statewide and then to a National platform. In early 2021, we received ethics and governance approvals for GlioNET expansion to the Western Sydney Local Health District (Westmead public and private hospitals) and Western NSW Local Health District (Orange, Bathurst and Cowra health services) and are discussing further possible GlioNET sites with clinicians at several other key health districts/hospitals.

New blood tests to diagnose and monitor brain tumours

Principal Investigators: Dr Kim (Kaufman) Alexander, Dr Susannah Hallal, Dr Brindha Shivalingam, A/Prof Michael Buckland, Dr Hao-Wen Sim

Glioblastomas (GBMs) are almost universally fatal brain tumours. Tumour recurrence is inevitable following standard treatment, and when tumours re-emerge they do so aggressively and usually have developed treatment resistance. With current monitoring approaches, tumour growth can be confused with common treatment-related brain changes. This is particularly problematic as patients may continue to receive an ineffective treatment or have an effectual treatment stopped prematurely.

Our research aims to address this problem by developing sensitive blood tests that can accurately measure GBM tumour activity. Extracellular vesicles (EVs) are stable nanoparticles released by all cell types, carrying molecules that reflect their cell of origin. Using our highly sensitive and innovative methods, we have shown that GBM tumours release EVs into the blood in sufficient quantities for accurate diagnosis and tumour subtyping. This means that we can access GBM molecular information via a blood test.

Despite a lengthy period with limited laboratory access, we have now processed and captured an enormous amount of data from 120 blood samples using two complementary research methods (SWATH proteomics and small RNA sequencing). These samples included blood taken at multiple time points from 35 GBM patients. The data analyses are well underway and we have received a grant from Sydney Informatics Hub that provides specialist biostatistics support to complete this research phase. From these complex ‘discovery’ analyses we aim to develop simpler tests that detect specific markers for GBM tumour progression and treatment response that importantly can be performed routinely by our hospital pathology department. We aim to use GlioNET study bloods and blood samples collected during the VERTU clinical trial to determine the robustness and accuracy of these new blood tests. The successful completion of this research will allow us to move towards a precision care model in the clinical management of GBM. This will reduce unnecessary neurosurgeries, better synchronise treatments for maximal therapeutic benefit and improve outcomes for patients.

As part of the analyses above, we also captured data from pre-operative blood samples from 24 patients with metastatic brain cancer, where tumours spread to the brain from another organ. Common primary cancers that result in metastatic brain cancer are breast, lung and melanoma. These cancers now have treatment options that can effectively target tumours in the brain without surgery. Yet, surgery is still performed as brain tumour tissue is needed for diagnostics. If our blood test methods can distinguish between different metastatic brain cancers and glioblastoma (primary brain cancer) before surgery, a proportion of patients may not need neurosurgery at all. Our pilot study results are very promising. It appears that we can distinguish patients with glioblastoma from those with metastatic brain cancer before surgery via our blood test. Furthermore, our test appears to separate patients according to the origin of their primary tumour, i.e., lung cancer versus melanoma. We are aiming to expand these studies to determine whether patients with new instances of brain cancer can be separated into optimal treatment streams without surgery.

 

Research programs

Publications

S. Hallal, S. Ebrahimkhani, H. Wei, M. Lee,  H. Sim, J. Sy, B. Shivalingam, M.E. Buckland and K.L. Alexander-Kaufman “Deep sequencing of small RNAs from neurosurgical extracellular vesicles substantiates miR-486-3p as a circulating biomarker that distinguishes glioblastoma from lower-grade astrocytoma patients” International Journal of Molecular Science 2020. 

S. Hallal, A. Azimi, H. Wei, N. Ho, M. Lee, H. Sim, J. Sy, B. Shivalingam, M.E. Buckland and K.L. Alexander-Kaufman “A comprehensive proteomics SWATH-MS workflow for profiling blood extracellular vesicles reveals an exciting new avenue for glioma tumour surveillance” International Journal of Molecular Science 2020.

A. Azimi, K.L. Kaufman, J. Kim, M. Ali, G.J. Mann and P. Fenandez-Penas, “Proteomics: an emerging approach for the diagnosis and classification of squamous cell carcinomas and its precursors” Journal of Dermatological Science 2020. 

A. Azimi, P. Yang, V. Howard, G.J. Mann, K.L. Kaufman and P. Fernandez-Penas, “Data independent acquisition proteomics analysis can discriminate between actinic keratosis, Bowen’s disease and cutaneous squamous cell carcinoma” Journal of Investigative Dermatology doi: 10.1016/j.jid.2019.06.128. 2020.

S. Hallal, S. Ebrahimkhani, B. Shivalingam, M. Graeber, M.E. Buckland and K.L. Kaufman, “The emerging clinical potential of circulating extracellular vesicles for non-invasive glioma diagnosis and disease monitoring” Brain Tumor Pathology 2019.

S. Hallal, D.M. Mallawaaratchy, H. Wei, S. Ebrahimkhani, B.W. Stringer, B.W. Day, A.W. Boyd, G.J. Guillemin, M.E. Buckland and K.L. Kaufman, “Extracellular vesicles released by glioblastoma cells stimulate normal astrocytes to acquire a tumor-supportive phenotype via p53 and MYC signaling pathway” Molecular Neurobiology, 2019.

S. Hallal, B.P. Russell, H. Wei, M. Lee, C.W. Toon, J. Sy, B. Shivalingam, M.E. Buckland and K.L. Kaufman, “Proteome profiling of extracellular vesicles from neurosurgical aspirates identifies Chaperonin Containing TCP1 Subunit 6A (CCT6A) as a potential glioblastoma biomarker with prognostic significance” Proteomics, Special Issue: Extracellular Vesicles and Exosomes 2019.

A. Azimi, M. Ali, K.L. Kaufman, G.J. Mann, P. Fernandez-Penas, “Tape stripped stratum corneum samples prove to be suitable for comprehensive proteomic investigation of actinic keratosis” Proteomics: Clinical applications, 2019.

A. Azimi, K.L. Kaufman, M. Ali, S. Kossard, P. Fernandez-Penas, “Differential proteomic analysis of actinic keratosis, Bowen’s disease and cutaneous squamous cell carcinoma by label free LC-MS/MS” Journal of Dermatological Science 91(1):69-78 2019.

 

Presentations

S Hallal, H Wei, M Lee, H Sim, B Shivalingam, M Buckland, K Alexander-Kaufman, “Comprehensive proteomic profiling of blood extracellular vesicles via SWATH mass spectrometry: a new avenue for glioma tumour monitoring”, 26th Annual Lorne Proteomics Symposium, Australia, 2021

KL Kaufman, “Extracellular vesicle biomarker research: towards a blood test for detecting and monitoring glioma tumours”, Mark Hughes Foundation Research Symposium, 2020

S Hallal, A Azimi, H Wei, B Shivalingam, M Buckland, K Kaufman, “SWATH-mass spectrometry as a biomarker discovery platform for comprehensive proteomic profiling of plasma-derived extracellular vesicles for glioma tumour monitoring”, Australasian Extracellular Vesicles Conference, Auckland 2020

KL Kaufman, “Exosomes in Glioma Research”, Neurosurgical Nursing Professional Development Scholarship Committee 16th Annual Conference 2019

KL Kaufman, S Hallal, H Wei, M Lee, H-W Sim, B Shivalingam, ME Buckland “Innovative ‘omics approaches reveal the exciting promise of extracellular vesicle profiling as a blood test for monitoring glioma patients” COGNO Annual Scientific Meeting 2019

A Batarseh, K Ekroos, S Hallal, KL Kaufman, “Enhancing extracellular vesicle isolation of human plasma verified by high resolution lipidomics” International Society for Extracellular Vesicles 2019

S Hallal, H Wei, B Shivalingam, M Buckland, K Kaufman, “Extracellular vesicles isolated from glioma tumour microenvironments provide miRNA markers for disease stage and tumour progression” Sydney Catalyst Postgraduate and Early Career Researcher Symposium 2019

S Hallal, A Azimi, H Wei, B Shivalingam, M Buckland, K Kaufman, “Establishing a SWATH-mass spectrometry biomarker discovery platform for comprehensive proteomics of plasma-derived extracellular vesicles for glioma tumour monitoring”Sydney Catalyst Postgraduate and Early Career Researcher Symposium 2019

Students
S. Hallal, PhD awarded 2019
A. Azimi, PhD awarded 2019
B. Kong, PhD candidate

New grants
H. Sim, H. Wheeler, Z. Lwin, K. Field, B. Chua, D. Espinosa, M. Buckland, K. Kaufman
MRFF rare cancer and diseases clinical trials
PICCOG: PARP and Immune Checkpoint inhibitor Combination for relapsed IDH-mutant high-grade Glioma
2019-2022 
$1.39M

K. Kaufman, B. Shivalingam, M. Buckland, H. Sim, S. Hallal
Mark Hughes Foundation Brain Cancer Innovation Project Grants
A new blood test to monitor glioblastoma patients and detect tumour progression
2020-2021
$200K

W. Varikatt, K. Alexander-Kaufman, M. Buckland
NSW Health Biospecimen Collection Grant
Sydney Brain Tumour Bank and GlioNET Observational study, Westmead site
2021-2024
$100K

K. Kaufman
Sydney Informatics Hub Project Scheme
Improving diagnostic and prognostic tests for glioblastoma patients
2021
$33K