Projects « Charlie Teo Foundation

Targeting Brain Cancer’s Body Clock

Researcher name: Prof Steve Kay
Institution: University of Southern California, U.S.
Grant name: Better Tools Grant
Grant amount: Up to $273K
Grant years: 2021-2023

Meet the Researcher

Prof Steve Kay is a chrono biologist, that is, he studies structures of time in living things. He has pioneered methods to monitor how genes are affected in real-time and characterised body clock (circadian rhythm) gene changes in plants, flies and mammals. He now combines his long-standing knowledge in circadian rhythm to determine whether this natural phenomenon can be used to treat brain cancer.

The power of the circadian rhythm in controlling how the body functions is just being understood. For example, it was only in 2017 that the Nobel Prize in Physiology went to scientists finding what controls the circadian rhythm. Now, only a few years later, we’re taking this knowledge, seeing whether it’s the missing link in understanding why targeted treatments are not working in brain cancer and already have a potential drug that may help to treat brain cancer.

GBM is always nearly fatal and even after surgery, chemotherapy and radiation therapy the tumour comes back growing from the stubborn brain cancer stem cells left behind which remain elusive to treat. But if these stem cells could be targeted and made more vulnerable to the different treatments, by shutting down their overactive biological clocks, then once the brain cancer is treated it could be cured.

Leveraging novel cryptochrome stabilizers to target GBM

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain cancer that originates from cells in the brain known as glial cells. The average survival time from diagnosis is 15 months. Treatment usually begins with surgery followed with chemotherapy and radiation. Although aggressive, standard-of-care has not been able to offer a cure for patients. One of the complications of GBM is that these tumours harbor so called cancer stem cells, called GSCs. GSCs are able to support the development and progressive growth of the GBM tumour given that they persist in the tumour microenvironment following surgical resection and are resistant to both chemotherapy and radiation. The laboratories of Drs. Steve Kay and Jeremy Rich have recently discovered that these GSCs harbor a unique dependence of circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK). These findings provide us with a novel therapy paradigm to explore in that we can now leverage small molecule drugs that negatively target the clock to selectively kill GSCs. There are currently two major classes of these compounds: CRY stabilizers and REV-ERB agonists. CRY stabilizers block the degradation of the Cryptochrome1/2 proteins, thereby inhibiting the gene expression effects of BMAL1:CLOCK. REV-ERB agonists suppress the expression of the BMAL1 gene. The Kay laboratory have been leaders in developing CRY stabilizers and we aim to utilise these compounds to target GSCs in cell culture models and GBM tumours in mouse models. Importantly, the CRY stabilizer SHP1705 from Synchronicity Pharma has demonstrated high tolerability and safety in Phase I studies in healthy volunteers. Findings from the proposed project will shed light on the efficacy of SHP1705 as a single agent or in combination with REV-ERB agonists or temozolomide chemotherapy against GBM, thereby providing us with Better Tools for the clinic.

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.

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.

‘Looking Inside’ Brain Tumours for a Cure

Researcher name: Prof Johanna Joyce
Institution: University of Lausanne, Switzerland
Grant name: Teo Research Rebels
Grant amount: $200K
Grant years: 2021-2023

Meet the Researcher

Prof Johanna Joyce is a cancer biologist and geneticist with over two decades of oncology research expertise and is a strong advocate and mentor for young scientists. She completed her PhD at the University of Cambridge, held several senior research positions across the globe and is currently leading her research laboratory at the Ludwig Institute for Cancer Research, University of Lausanne, Switzerland. Prof Joyce’s laboratory studies brain cancers by literally ‘looking inside’ tumours to find ways of harness the immune system to fight the cancer.

 

Prof Joyce’s laboratory has developed a pioneering technology that allows scientists to visualise the tumour in living subjects in real-time. By employing these methodologies, Prof Joyce explores uncharted territory into how brain tumours evolve over time.

Currently, most brain cancer patients follow similar treatment plans. Identifying how a brain tumour evolves over time will improve our understanding of both what to treat and when to treat the cancer, offering opportunities to develop new therapeutic targets and treatment strategies.

Illuminating the brain tumour microenvironment: gaining new insights into gliomas through intravital imaging and molecular MRI

Brain tumours represent some of the most aggressive forms of cancer. The brain is our most critical organ, controlling every aspect of who we are as humans, and therefore brain tumours are also amongst the most feared of all cancers. Eighty percent of tumours that develop within the brain are gliomas, with over half being glioblastoma, the most malignant form of this disease. Unfortunately, despite treatment with standard of care therapy (surgery, radiation and temozolomide chemotherapy), glioblastomas are essentially incurable, and the 5-year survival rate for patients with the most aggressive gliomas remains <5%. This dismal clinical outcome underscores the urgent need for novel perspectives and effective therapeutic strategies to treat patients with this disease. We have been tackling this challenge in my lab for several years, and have taken the strategy of deeply exploring the brain tumour microenvironment (TME) as a means to exploit the knowledge we gain to develop new therapies. Since cancers and their TME are highly dynamic and co-evolve during tumour progression and in response to treatment, it is necessary to study cancer as it develops - in real time and in situ, in all its complexity. Therefore, my lab has now developed a strategy using the unique power of intravital microscopy (IVM) and molecular MRI to literally ‘look inside’ the brain of living animals in a longitudinal manner; a first in the cancer field.

Harnessing AI to Halt Brain Cancer

Researcher name: Dr Guillermo Gomez
Institution: University of South Australia, AUS
Grant name: Teo Research Rebels
Grant amount: $200K
Grant years: 2021-2023

Meet the Researcher

Dr Guillermo Gomez is a cancer cell biologist and completed his PhD in cell biology at the National University of Cordoba, Argentina in 2008. His laboratory is globally recognised for studying brain cancer cell behaviour and over recent years has developed several tools to analyse how brain cancer cells and surrounding healthy brain cells interact. He has honed his expertise here in Australia at the University of South Australia and developed a powerful method of combining artificial intelligence with state-of-the-art 3D brain tumour models to study brain cancer.

Studying the tumour microenvironment in brain cancer is incredibly complex – there are few tools at hand and significant variation in current experimental models. This project has two key game-changing aspects: (1) to use artificial intelligence to analyse vast volumes of existing tumour images not easily capable by humans and (2) using a novel tool developed by Dr Gomez to re-create, cultivate and analyse the tumour in a 3D model called an organoid. This combination will enable Dr Gomez and his team to identify new therapies for brain cancer patients.

Few therapies are available and approved for use in brain cancer. By exploring a paradigm shifting approach to treating brain cancer, that is, to disrupt the tumour and it’s environment, this project will offer new treatments and strategies for brain cancer patients.

Harnessing artificial intelligence to develop new therapies for glioblastoma

While the survival rates of most cancers have dramatically improved in the last few decades, this is not the case for brain cancers, where the 5-year survival has hardly changed for 30 years, remaining around 20%. For glioblastoma, the most diagnosed malignant brain cancer in adults, the statistics are far worse, with a 5- year survival of just 5%. Despite recent advances in understanding some of the critical drivers of glioblastoma formation and progression, this knowledge has not yet translated into improvements in glioblastoma therapy. This lack of progress in the clinical setting is mainly due to the highly heterogeneous nature of glioblastoma and the ability of tumour cells to switch transcriptional programs in response to the interactions with cells in the tumour microenvironment, which leads to therapy resistance and tumour recurrence. Thus, targeting the interaction of tumour cells with non-malignant cells in the tumour microenvironment has recently emerged as an exciting anti-cancer approach in glioblastoma.