The Australian Brain Cancer Research Alliance (ABCARA) officially launched on October 24th, 2021 with our inaugural Symposium. ABCARA is an alliance of adult brain cancer focused researchers, clinicians and clinician scientists that believe improving outcomes for brain cancer patients requires an increased and sustained collaborative effort that shares scientific resources, knowledge and expertise. This will then result in increased translation of novel discoveries into the clinic, as well as maximise the insights gained from clinical trials.
We had hope to gather in person for the Symposium, but the realities of Covid-19 had us move to a virtual platform. There were 180 registrants for the day, a number that pleasantly surprised even the organisers, and highlighted the appetite for meetings with a strong science focus and for forming a national collaborative. The Symposium focused on the challenges and opportunities for brain cancer research in Australia.
The Symposium was opened by Prof Hui Gan (ONJCRI), an ABCARA Co-Director, who welcomed participants and introduced the ABCARA’s vision before an outstanding program that highlighted the breadth and depth of talent and expertise in Australia.
The formal talks commenced with ABCARA Co-Director, Prof Bryan Day (QIMR) who highlighted his work on defining Eph receptors as tumour specific targets in both adult and paediatric brain cancer. This work focussed on two particular family members, EphA3 in adult glioblastoma and EphB2 in medulloblastoma, indicating a functional role in promoting tumourigenesis in these aggressive cancers. Eph receptors are attractive therapeutic targets because they are discretely expressed on the tumour and not the normal brain, making them ideal candidates for approaches such as antibody drug conjugate design and CAR-T cells.
There were two talks discussing the role of ion channels (surface proteins that allow the passage of small ions in and out of the cell) in glioblastoma (GBM). Dr Emily Fletcher (Telethon Kids) discussed how our view of GBM has changed over the past few years. We now know that GBM is an electrically active cancer that integrates itself with neurons. Dr Fletcher shared data showing that several sodium channels are expressed in GBM cells and could serve as drug targets that might disrupt the interaction between GBM cells and neurons. Computational Biologist, Dr Anya Jones (Telethon Kids), presented a systems biology approach to studying the underlying gene networks driving GBM. Genes do not function in isolation but as an orchestrated network driving proliferation and disease progression. Using this approach, Dr Jones showed that GBM cells ion channels are central to several signalling pathways that give GBM cells an advantage to survive and become resistant to targeted therapies. Ongoing network analysis may identify ion channels with critical roles in these pathways, which then in turn, could be disrupted with repurposed ion channel drugs.
Dr Guillermo Gomez’s (Centre for Cancer Biology, SA) presentation highlighted his work using artificial intelligence (AI) applied to GBM histopathological images. His results showed how AI analysis can help predict patient survival and define different tumour regions, including central, infiltrating, and microvascular proliferation regions. He also presented data on a new spatial atlas of GBM representing the cellular composition and tumour-stroma interactions. He concluded his talk with an overview of new patient-derived glioblastoma explant organoids that better recapitulate the cellular composition of the primary tumour than cell lines. Both Prof Geraldine O’Neill (The Children’s Hospital at Westmead) and Prof Bryan Day also presented initial data on their organoid technology, highlighting the interest in this rapidly developing technology for brain cancer research.
Our invited international speaker Prof Roel Verhaak (The Jax Cancer Centre), who is also a key leader within the Glioma Longitudinal AnalySiS (GLASS) consortium, gave a stunning update on some of the consortium’s recent research. Using 190 paired primary and relapsed GBM samples, the consortium studied the genetic impact of radiotherapy (RT) on GBM cells. They showed that RT increased the burden of both small and large deletions. Detailed analysis implicated classical non-homologous end-joining-mediated DNA damage repair mutagenesis following RT as a key cause of these deletions. Provocatively, he presented strong evidence that this RT induced damage is unfavourable to patient survival. One implication of the research is that targeting DNA repair may significantly enhance the response to RT 1.
Prof Hui Gan opened our clinical session by emphasising the challenges but also the great opportunities in neuro-oncology clinical trials. For investigator-initiated trials, having more input from basic and translational researchers will maximise the knowledge and benefit from clinical trials, especially in the understanding of resistance in negative trials. Prof Andrew Scott (ONJCRI) focuses on previous successes and current work at the ONJCRI Centre for Research Excellence in Brain Cancer in developing new therapies, molecular assays and imaging approaches for brain cancer. He described recently developed imaging probes that are being used to better understand blood-brain barrier physiology and drug delivery, including the FIG study looking at the use of FET-PET for patients with glioblastoma. He also outlined drugs that had been successfully commercialised and translated from their institute into the clinic, resulting in drugs like Depatuxizumab mafodotin and Ifabotuzumab.
Dr Kimberley Alexander (Chris O’Brien Lifehouse) introduced us to ‘GlioNET’, a new longitudinal biobanking and clinical registry study for newly diagnosed glioma patients recently piloted in the Sydney Local Health District. GlioNET aims to build a free-access research platform comprising complete sets of longitudinal clinical data and biospecimens captured from glioma diagnosis until death. In the first 18 months, they enrolled 44 glioma patients, preserved tumour tissues and living cells from 48 neurosurgeries, and archived 1128 plasma and serum cryovials. Clinicians and researchers interested in joining the GlioNET-work should contact ([email protected]).
In his second talk, Prof Bryan Day discussed his work on the development of the QCell primary brain cancer model resource. This well characterised panel of 12 primary brain cancer models has been published in over 50 scientific research articles and has driven brain cancer discoveries all around the world. QCell models are freely available to the scientific community to undertake academic discovery-based research (access here).
Dr Jasper de Boer (VCCC Alliance) was our final invited speaker and spoke about histone 3.3 gene mutations that are the drivers in paediatric DMG (DIPG) and in approximately 40% of adult midline gliomas. He described three High-throughput screening (HTS) platforms designed to exploit the histone dependent vulnerabilities of these cancers and identify therapeutically targetable dependencies.
We received some outstanding abstracts. Congratulations to poster prize winners:
- Dr Ashray Gunjur was awarded Best Student Poster for “Poor correlation between preclinical and phase 1 trial results for tumour targeted therapies in relapsed glioblastoma: the results of a systematic review”;
- Dr Lachlan Harris won the Most Innovative Research Award for “Prolonging for survival in glioblastoma by targeting quiescence” and
- Dr Michelle Li was judged Best Overall Poster for “EphB Receptors as Potential Therapeutic Targets for Paediatric Medulloblastoma”.
In addition to the great attendance and participation by the attendees, support for ABCARA was demonstrated by the great assistance received from our partners and sponsors. The Symposium was supported by our partner the Cooperative Trials Group for Neuro-Oncology (COGNO), and finished with a message from A/Prof Eng-Siew Koh (UNSW), the current COGNO Chair, who expressed her support for the two organisations to work closely together to make a difference for patients with brain cancer. In addition, the Symposium was endorsed by the Olivia Newton-John Cancer Research Institute (ONJCRI) and the Victorian Comprehensive Cancer Centre (VCCC) Alliance, including the sponsorship of the VCCC for the prizes awarded.
We look forward to building this community of like-minded researchers across the country, and ultimately internationally. Please visit our web page for further details and you can also contact us there if you are interested in becoming a member (www.abcara.com)
Co-Directors
*Terrance Johns (Telethon Kids Institute)
Hui Gan (Olivia Newton-John Cancer Research Institute)
Bryan Day (QIMR Berghofer)
*Correspondence: [email protected]
Reference:
Kocakavuk, E., et al. Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet 53, 1088-1096 (2021).
Source: ABCARA