The Isabella and Marcus Foundation is funding a new clinical trial for DIPG and Diffuse Midline Gliomas in children and young adults in Australia and New Zealand. The trial opened in August 2022 and will initially evaluate a promising new drug combination of ONC201 and paxalisib. Treatment is available for DIPG and other Diffuse Midline Glioma’s at initial diagnosis, following radiotherapy or at time of progression. The trial is being conducted by the Australian and New Zealand Children’s Haemotology/Oncology Group and is co-sponsored by the International Pacific Pediatric Neuro-Oncology Consortium. Funding partners include Australian Communities Foundation, RCD Foundation, the Australian Brain Cancer Mission and the Wayne Francis Charitable Trust. A media release is available at: https://tinyurl.com/4vked7u8
The Isabella and Marcus Foundation, in partnership with Cure Brain Cancer Foundation funded the Australasian participation in the ‘International BIOMEDE (Biological Medicine for Diffuse Intrinsic Pontine Glioma Eradication) study’ from 2018-2020. This clinical trial was available to treat 24 children in Australia and New Zealand newly diagnosed with DIPG as part of a worldwide cohort of 250 children. The study evaluated the efficacy of 3 drugs in combination with radiotherapy. The choice of drug was determined by the mutation(s) found in a biopsy of each child’s tumour, with each drug specifically acting on one type of mutation commonly found in DIPG. The study was conducted by the Australian and New Zealand Children’s Haematology/Oncology Group and was led by Dr Geoff McCowage at the Children’s Hospital at Westmead, Sydney.
The Isabella and Marcus Foundation is a member of the International DIPG Collaborative, one of over 30 like-minded charities around the world that collaborate to fund DIPG/DMG projects. The annual contribution from the Isabella and Marcus Foundation supports the annual conference and Australian research.
The Isabella and Marcus Foundation provides seed funding for DIPG projects, providing researchers with an opportunity to start research that wouldn't otherwise be funded. The data generated can then be used to apply for large government grants that will accelerate research to develop treatments for DIPG and other Diffuse Midline Glioma's.
Immunotherapy is an exciting recent development for the treatment of cancer, with proven efficacy for a number of cancers. Dr Misty Jenkins and her team of researchers from WEHI (formerly the Walter and Eliza Hall Institute of Medical Research) is developing CAR-T cell therapy, which supercharges the child’s own immune system so that it can effectively destroy DIPG cells. The treatment will involve taking a sample of blood from the child, purifying the immune cells, which are re-engineered in the laboratory to recognise and kill DIPG cells and then infused in large numbers back into the child.
Dr Lee Wong
Dr Wong specialises in telomeres, which are complexes found at the ends of chromosomes that are absolutely essential for maintaining chromosome stability. Each time a cell divides, telomeres become shorter and when the cells have gone through many divisions the telomeres become so short that the cells die. This is a protective mechanism against cancer because mutations can accumulate after many cell divisions. However, in some cancer cells, the telomeres do not shorten because an enzyme called telomerase is expressed at higher than normal levels or because a series of molecular events called "Alternative Lengthening of Telomeres (ALT) is turned on. This ALT pathway is common in brain tumours. Most children with DIPG express a mutation that is associated with the ALT pathway. This study investigated the link between this mutation in a Histone 3.3 gene and switching on the ALT pathway.
Brain Cancer Biobank
Brain cancer researchers need ready access to samples for study. Tissue specimens from children are rare and finding appropriate samples in institutions around the country is difficult. Procedures to access samples also differ across the various institutions. Linking the various biobanks across Australia into a single network and portal will enable research by providing ready access to specimens.
‘Brain Cancer Biobanking Australia’ is an initiative of Robyn Leonard (Founder) whose daughter Lucie died from brain cancer. The Isabella and Marcus Fund supported this initiative from 2016 to 2019.
Dr Pouya Faridi
Therapeutic cancer vaccination is an emerging approach for incurable cancers. They can train the immune system to find and destroy tumours. However, the most challenging part of any vaccination strategy is identifying an appropriate vaccine target on the surface of a tumour. Dr Faridi and his team have developed new technologies to identify novel targets for cancer vaccines. His laboratory uses proteomics, immunopeptidomics and systems biology techniques to discover novel proteins and peptides as DIPG-specific vaccine targets. They use preclinical models, patients’ tumours, and blood samples for vaccine target identification. The ultimate goal of his laboratory is to develop off-the-shelf vaccines for DIPG patients. These vaccines might be used as monotherapy or combined with other treatment strategies such as radiotherapy and epigenetic modulators.
Dr. Jason Cain
The Hudson Institute
Over the last 10 years our understanding of the genetic and molecular landscape of DIPG has greatly improved. As a result, great effort has gone into trying to identify potential new therapies using DIPG cell culture models but despite promising results, these treatments have had limited effects on DIPG growth in living models and/or in patient clinical trials. The failure to successfully apply findings from DIPG cells grown in plastic culture dishes in the laboratory could be explained by the likelihood that these cells function differently in culture than in the brain, and therefore respond differently to treatment. Dr Jason Cain and his PhD student, Shaye Game (Elliot Gautsch Scholar) are undertaking novel genetic screens to identify pathways required for DIPG survival in clinically relevant DIPG models that can be targeted by existing drugs that are currently used for other diseases.
Jeff is preparing pre-clinical models of DIPG that recapitulate the disease that occurs in children. In its first iteration the model will incorporate the 2 most common mutations observed in children, which are thought to drive the development of the tumour. These mutations, H3.3 K27M and p53 have been genetically introduced into the DNA of the model and sit alongside the normal genes, which are functional until they are replaced by the mutated genes by introducting tamoxifen into the drinking water. A reporter gene, also under the control of tamoxifen, has also been introduced to highlight the area(s) of the brain that express the mutations.
All of the genetic modifications have been introduced. The model is now being evaluated to determine if the mutations trigger the development of DIPG. The model will then be provided to a central repository as a resource for all DIPG researchers worldwide to help fast track treatments.
This work is co-funded by Brainchild Foundation.
The charity regularly sponsors scientific meetings that bring DIPG/DMG researchers together to share their knowledge. Scientific exchange provides an impetus for scientific progress and encourages collaborations between laboratories. In 2019, the Isabella and Marcus Foundation sponsored the International DIPG Symposium in Sydney. In 2019 and 2023 sponsorship was provided to the the 'Cell Signalling and its Therapeutic Implications: Focus on Cancer' conference. Each year, it supports the Childhood Cancer Research Symposium at the Hudson Institute of Medical Research.
Our scholarship program addressed the historical shortfall in scientists that study DIPG/DMG. The charity is providing PhD scholarships to graduate students, some of whom will become the next generation of paediatric brain cancer scientists. These scholarships are named in memory of children who lived with DIPG. 10 scholarships have been funded so far in partnership with Upstream Foundation.
The Isabella and Marcus Foundation is a member of a the 'Low Survival Cancers Alliance' committee, chaired by the Cancer Council Victoria. The committee advocates for increased funding for cancers with 5 year survival rates below 50%. In Victoria, these cancers represent 20% of all cancer diagnoses but encompass 50% of cancer deaths.
The committee was established in March 2016. Advocacy resulted in $1.5 million in funding by the Victorian government, which was backed by a further $1 million dollars from the Cancer Council of Victoria.
In 2017 the Isabella and Marcus Foundation was invited to present before the Federal Senate Select Committee investigating Funding for Research into Cancers with Low Survival Rates.
Low Survival Cancers Alliance
Professor Peter Rogers University of Melbourne
Conventional radiotherapy is a routine palliative treatment for children with DIPG and provides a temporary reduction in symptoms. Children typically receive 30 treatments over 6 weeks. But conventional radiotherapy is not curative and no other treatments are available. Microbeam radiation therapy is a novel, experimental radiotherapy in which X-rays are generated from a synchrotron. This form of radiotherapy delivers higher doses of radiation in a SINGLE treatment and the beams are shaped to reduce damage to the healthy tissues of the brain. It is being investigated as a curative treatment for DIPG and has shown early promise.
This study demonstrated that doses 20 times higher than conventional radiotherapy could be delivered safely. This exciting finding paves the way for additional studies in preparation for future clinical trials.
This pilot project comprised a multidisciplinary group including physicists, radiotherapists and cancer biologists. A follow up study is planned to examine the efficacy of this treatment for DIPG relative to conventional radiotherapy.