Projects « Charlie Teo Foundation

Unshackling the Immune System

Researcher name: A/Prof Peter Fecci
Institution: Duke University, U.S.
Grant name: More Data Grant
Grant amount: Up to $477K
Grant years: 2021-2023

Meet the Researcher

A/Prof Peter Fecci is a neurosurgeon, scholar and brain cancer researcher. He has trained at the Ivy League research University, Cornell University, and prestigious Duke University (U.S.). His research centres around brain tumour immunology, immunotherapy and T-cell dysfunction in glioblastoma. He was one of the first to identify T-cell dysfunction in brain cancer.

After decades of failure, scientists finally found effective ways of turning the immune system against cancers, with spectacular results – except for brain cancer. Immunotherapies have continued to fail in brain cancer and the team have discovered that the T-cells are stuck in the bone marrow of brain cancer patients. This project may unlock the reason why immunotherapy has failed in brain cancer and lead to immunotherapy treatments finally being effective.

 

If the team’s theory is correct, this work will finally allow for the development of effective immunotherapies for patients with brain cancer.

Development of Beta-arrestin 2 small molecule inhibitors for brain cancer therapy

Cancers of the intracranial (IC) compartment carry unique therapeutic challenges and offer grim outcomes, regardless of tissue type. These cancers include primary malignancies, such as universally lethal glioblastoma (GBM), as well as far more common brain metastases. Our group unveiled the ability of IC tumours to cause a dramatic plunge in the number of circulating T-cells, the main cells that help drive the body’s defences against cancer. Immunotherapy is a novel modality of cancer therapy that has gained momentum in recent years, which works by harnessing and ramping up the body’s own immune system, especially T-cells (the immune system’s effector arm) to fight cancer. However, without T-cells, there is nothing for immunotherapy to act upon. Our group tracked the missing T-cells in patients with IC cancers and discovered them ‘trapped’ in the bone marrow. We showed that this phenomenon is accompanied by loss of sphingosine 1-phosphate receptor 1 (S1P1) from the T-cell surface. S1P1 is a molecule which would normally act as an ‘exit visa’ allowing T-cells to exit from the bone marrow. Without surface S1P1, T-cells instead are locked in, unable to circulate out of the marrow. To solve this problem, our group demonstrated that mice lacking Beta-arrestin 2 (βARR2), an adaptor protein responsible for S1P1 internalisation, do not experience sequestration, and their T-cells are instead able to travel to the brain, and, with the help of immunotherapy, fight their cancers. Our studies in mouse models provided the proof of concept that blocking βARR2 and preventing loss of S1P1 could promote T-cells travelling to the brain to produce anti-tumour responses. However, we’ve now found that inhibiting βARR2 does far more to combat cancer, and we’re finding unprecedented responses against many types of cancer when we knock out βARR2. We think we’ve uncovered an entirely novel cancer therapeutic, and we’ve partnered with a Nobel Laureate who is an expert in this molecule to help develop a pharmacological strategy to block βARR2. We hope that our continued work will allow for the development of more effective immunotherapies for patients with brain cancer.

A New Drug for GBM

Researcher name: Dr Alan Wang
Institution: MD Anderson Cancer Centre, U.S. and Pharmaxis, AUS
Grant name: Better Tools Grant
Grant amount: Up to $186K
Grant years: 2021-2022

Meet the Researcher

Dr Y. Alan Wang is a cancer biologist at one of the most prestigious comprehensive cancer centers in the U.S., MD Anderson. He trained at Harvard Medical School and his team has been responsible for identifying the cause of some types of cancers.

Brain cancer has only had 5 FDA approved treatments in the past 35 years, while some cancers have around 34, like breast cancer! We desperately need to trial more treatment options for brain cancer patients.

If the work from this project shows that this novel drug works to make the brain cancer more susceptible to attack by the immune system and extends survival in these preclinical brain cancer models, then this is the necessary data needed to get the drug into a Phase I clinical trial.

Evaluation of Pharmaxis LOX inhibitor in recurrent GBM

Glioblastoma (GBM) is the most common and lethal primary brain cancer with limited therapeutic option. Surgery and radiation are the two most common therapeutics for these patients and recurrences following these interventions almost always occur leading to a dismal 5-year survival rate of less than 5 %. Targeted therapeutic approaches on disease drivers have also generated limited success due to a lack of blood brain barrier penetrating drugs and tumour cells often develop resistance mechanisms to targeted therapy. In the past decade, our lab has been focused on the tumour microenvironment, composed mostly of tumour infiltrating macrophages in GBM. We have shown recently that PTEN (a tumour suppressor frequently lost in GBM) deficiency induced specific macrophage recruitment and we have provided concrete evidence that macrophage recruitment is largely due to the production of LOX by tumour cells. We demonstrated that inhibition of LOX at pharmacological and genetic levels can significantly extend survival of GBM-bearing animals. Immunotherapy has failed in GBM patients due, at least in part, to PTEN deficiency, and the fact that PTEN deficiency dependent infiltration of macrophage acting as an immune suppression mechanism and recurrent GBMs are often infiltrated with macrophages, we propose to test whether LOX inhibitor can significantly prevent GBM recurrence in patients undergoing surgery and chemoradiation therapy. In collaboration with Pharmaxis, we will test whether the LOX inhibitor PXS-5505, which has already shown safety profile in the phase 1 trials, would inhibit LOX mediated macrophage migration in tumour model in vivo, block GBM recurrence in GBM animal models, and synergize with immuno-checkpoint inhibitors to cure GBM in animal models.

Starving Brain Cancer

Researcher name: Prof Jeff Holst
Institution: UNSW Sydney, AUS
Grant name: More Data Grant
Grant amount: Up to $136K
Grant years: 2021-2022

Meet the Researcher

Prof Jeff Holst is a highly experienced cancer researcher who has turned his efforts to brain cancer. He completed his postdoctoral studies at the prestigious St Jude Children’s Research Hospital (U.S.) before returning to Australia to start his own cancer laboratory. His research has led to ground-breaking new techniques in cancer immunology and metabolism.

This research will build upon the work of our Cancer Genomics – The Next Level project as the data collected on the energy sources needed by brain cancer cells will be integrated and matched with the genetic data, creating the ultimate roadmap of what and how cancer cells grow, survive and ultimately how they can be destroyed.

 

It will enable us to understand how GBM tumours are metabolically programmed, providing the critical data for future studies in developing new therapies targeting these metabolic vulnerabilities.

Developing a metabolic roadmap to discover novel therapeutic avenues to starve GBM

Glioblastoma (GBM) is the most aggressive primary brain tumour with an overall survival prognosis of less than 15 months - a devastating diagnosis for both the patient and their family. Over many years, researchers have tried to map the genetics of the disease, in order to determine new ways to treat GBM based on genetic changes such as mutations. Despite this, there remains no effective treatments for GBM, with surgery, chemotherapy and radiation therapy the current options, suggesting we need to try an alternative avenue.

While genetic changes in the DNA have a profound effect on cancer cells, these effects are actually carried out by proteins which the DNA codes for. In turn these proteins, including nutrient transporters and enzymes, combine together to mediate the uptake and metabolism of nutrients in order to facilitate the rapid growth of the cancer cells. This is critical, as a cancer cell needs to essentially double all its DNA, RNA, proteins and fats in order to make two new cells during cell division. This cell division occurs rapidly in GBM, increasing the size of the tumour and ultimately tumour relapse post-treatment.

In this pilot study, we will undertake metabolic profiling of GBM patient samples taken at surgery, to understand how they use and distribute their essential nutrients. This will develop a metabolic roadmap which can be combined with genetic information being developed through the Cancer Genomics – The Next Level project. Ultimately, success in this project will enable us to understand how GBM tumours are metabolically programmed, providing the critical data for future studies developing new therapies targeting these metabolic vulnerabilities. These future studies would include using our patient-derived laboratory models to test currently available metabolic drugs, thereby determining whether they can successfully starve the GBM cells.

The Evolution of Childhood Brain Cancer

Researcher name: Dr Roel Verhaak
Institution: The Jackson Laboratory, U.S.
Grant name: More Data Grant
Grant amount: Up to $672K
Grant years: 2020-2021

Meet the Researcher

Dr Roel Verhaak is a world-class brain cancer researcher. He trained, in part, at the prestigious Broad Institute of Harvard and MIT Institutes in Cambridge (U.S.) and the Dana-Farber Cancer Institute in Boston (U.S.). His research contributed to the definition of clinical categories of brain cancer that are now used by the World Health Organisation.

Experimental models have been extremely useful for learning about cancer and how we might treat it. For brain cancer, however, these models have failed to provide sufficient insight for a breakthrough. This project will use data to help understand what drives brain cancer from models of naturally occurring brain cancer that have never before been explored.

This work could be the beginning of a significant new frontier in brain cancer treatment for children. Striving to treat and cure dogs with cancer, learning what works best and importantly why it works, can inform our own therapy regimens. This provides an important opportunity to improve a child’s brain cancer outcome.

Targeting regions of converging synteny and loss of heterozygosity in paediatric and canine glioma

Brain cancers such as glioma occur in dogs at rates comparable to humans, with short-snouted breeds such as boxers being more susceptible than others. In helping to treat dogs diagnosed with brain cancer, the research team compared the molecular and cellular characteristics of glioma in dogs to their human counterparts and found extensive similarity in particular to aggressive glioma observed in children.

In this project, the team will leverage the similarities between glioma in dogs and in children to further sharpen the lens as to what is causing these cancers. They will mine large datasets on dog and children’s gliomas to precisely define the hundreds of molecular abnormalities found in both disease types. The team will perform a large screen and functionally eliminate each molecular abnormality one by one and evaluate the effects of this depletion on cancer-associated features such as cell growth in human and canine cell models of glioma. This advanced screen is enabled by the versatile and cutting-edge imaging platform and computational expertise at the Jackson Laboratory.

The team expects to see convergence of the most impactful molecular abnormalities on brain cancer’s evolutionary mechanisms, which will implicate that these mechanisms are candidates for the development of new treatments.

Nasal Drug Delivery to the Brainstem for DIPG/DMG

Researcher name: A/Prof Hong Chen
Institution: Washington University, U.S.
Grant name: Alegra’s Army Grant
Grant amount: Up to $714K
Grant years: 2020-2023

Meet the Researcher

A/Prof Hong Chen is an expert in focused ultrasound. Her passion began as an undergraduate student after a visit to a Chinese hospital, where she saw patients lining up for the focused ultrasound treatment. That image remained burned in her mind and she centred her future research career to developing focused ultrasound as a diagnostic and treatment tool for brain cancer. 

The project explores a new method to bypass the brain’s natural shield (the blood-brain barrier) and deliver drugs right to the tumour and at the exact dose needed to treat the cancer. The team has already proven this method successful; and this project is the last step before we can help pipeline this to early phase clinical trial for brain cancer patients.

This is the first project to develop a nasal spray to non-invasively deliver drugs to the brain. It pairs several technologies – nanoparticles which house the drug – focused ultrasound and microbubbles which directs the drug containing nanoparticles to where they need to go in the brain – all via delivery through the nose.

Drug therapy for brain cancer is challenging because the blood-brain barrier makes it difficult for drugs to penetrate and accumulate at the right dosage needed to have an effect. This potential new method provides a non-invasive and effective way to get the drugs right to where they need to be working.

Focused ultrasound-mediated intranasal delivery for non-invasive drug delivery to the brainstem with minimised systemic exposure in a large animal model

Diffuse midline gliomas (previously known as diffuse intrinsic pontine glioma) is the deadliest paediatric brain cancer that often occurs at the brainstem. It has a median survival from the time of diagnosis of only 9 months and 100% mortality rate, a dismal prognosis that has remained unchanged over the past 40 years.

To address the unmet and urgent need for innovative technology to improve diffuse midline glioma treatment, this project proposes to develop a novel drug delivery technique – focused ultrasound -mediated intranasal delivery (FUSIN). FUSIN utilises the intranasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier and minimising systemic exposure. FUSIN also utilises focused ultrasound to induce microbubble cavitation (expansion and contraction of microbubbles) within the focused ultrasound focal zone, leading to enhanced transport of intranasal-administered agents to the focused ultrasound -targeted brain location.

Compared with currently available techniques, FUSIN is unique in that it can achieve non-invasive and spatially targeted brain drug delivery while minimising toxicity in other organs. Our previous studies already demonstrated successful delivery of various agents to different brain locations using FUSIN in a mouse model. The objective of this application is to evaluate the feasibility and safety of FUSIN to obtain compelling preclinical evidence needed to support an early phase clinical trial.