Clinical Trial Lighting Up Hope For Brain Cancer Patients

A breakthrough trial targeting Glioblastoma, one of the most aggressive and deadly forms of brain cancer, is giving hope to patients and their families after successful initial clinical results.

 

Brain cancer, in particular Glioblastoma, is one of the most challenging forms of cancer to cure. There are limited options for treatment and for most, it’s deadly.

An ONJCRI-sponsored trial funded by the Cure Brain Cancer Foundation, and with study drug provided by Humanigen, is hoping to change that, by targeting the microenvironment within brain cancer with a new humanised antibody called ifabotuzumab (formerly KB004). Head of the ONJCRI Tumour Targeting Program, and lead molecular imaging and scientific investigator, Professor Andrew Scott said that the phase 1 trial, completed in 2021, was a world first and has shown some highly promising results.

“The trial itself explored the safety and bioimaging of using ifabotuzumab in patients diagnosed with Glioblastoma,” said Professor Scott. “This antibody has been evaluated in patients with blood cancer in the past, but it has never been evaluated in patients with solid tumours and certainly not brain cancer. Ifabotuzumab is unusual because by targeting the EphA3 receptor, it doesn’t just attach to cancer cells, it also attaches to the microenvironment that exists within the cancer.”

The team set out to develop an innovative imaging approach where they tagged ifabotuzumab with a radioactive positron emitting tracer. This allowed the team to image where the antibody moved throughout the body using positron emission tomography (PET) and demonstrated that ifabotuzumab selectively targeted the sites of the tumour in the brain.

“We were very excited because not only were we able to demonstrate ifabotuzumab’s safety, but the results were even better than we anticipated. By tracing ifabotuzumab in this way, we were able to observe that high concentrations of the drug went directly into the site of the tumour without inadvertently binding to healthy tissue. To our delight, images of every single patient in the trial showed the tumours lighting up, which is significant.”

Professor Hui Gan, Clinician-Scientist, and Co-Director of the Centre for Research Excellence in Brain Cancer at the ONJCRI was the oncology lead for the trial and was equally impressed.

“Glioblastoma is a very aggressive form of brain cancer, with no treatment shown to prolong survival at the time of inevitable relapse. These results are very encouraging, and Ifabotuzumab should further be developed as a new treatment for patients.”

This project has been a great example of translational research and highlights the crucial need for collaboration between laboratory researchers and clinicians to gain the best possible outcome for cancer patients.

“Not only did the collaboration between scientists and clinicians directly lead to the rapid translation of ifabotuzumab into the clinic, the on-going collaboration has allowed myself and my clinical team to feed our observations back to the laboratory and this is helping us develop the next generation of these drugs.”

While the trial was a joint effort between both Professor Gan and Professor Scott, many people have been involved in the process.

“It really has been a team effort,” says Professor Scott, “Professor Peter Janes, Head of the Receptor Biology Laboratory, Dr Jodie Palmer, Clinical Projects Manager, and Drs Christian Wichmann and Ingrid Burvenich along with the rest of the Tumour Targeting Laboratory have all been instrumental in getting to this point.”

This project has really come full circle for Professor Scott, who was central to the original development of ifabotuzumab.

“An interesting part of the story is that the development of the antibody originally came from a collaboration established between myself and two collaborators Professor Andrew Boyd (WEHI and QIMR) and Professor Martin Lackmann (Monash University) some 15 years ago, and after extensive research the antibody was licensed to the US biotech company, Humanigen, and has been developed into the drug ifabotuzumab.”

“To see something that you spent a long time developing, tested in this way is very gratifying, but to then to see the results in the first patient and achieve results better than I was hoping for is a very proud moment. It’s been a great journey, but it’s also just part of the journey. We now need to try and take it to the next level.”

On the back of the trial’s success, the ONJCRI and Humanigen are now working together on developing an ifabotuzumab-based antibody drug conjugate that they will then take into a first in human clinical trial by the end of 2023.

“After the initial trial, we and Humanigen decided that ifabotuzumab is an ideal candidate to deliver cancer killing drug payloads to cancers, including brain cancer but also other cancers such as lung cancer, colon cancer and breast cancer. The next phase of clinical trials will include a range of patients with these conditions, so we really hope that these drugs will become an effective treatment for patients with a range of devastating cancer diagnoses.”


Professor Andrew Scott awarded national grant to target Triple-Negative Breast Cancers

Professor Andrew Scott, Head of ONJCRI’s Tumour Targeting Program has been awarded an Investigator Initiated Research Scheme (IIRS) grant from the National Breast Cancer Foundation (NBCF) to investigate how effective the 6B3 antibody is at treating triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for around 10-15% of all breast cancers. TNBC differs from other types of breast cancer in that it is more aggressive, has fewer treatment options, and unfortunately has one of the highest rates of recurrence.

“TNBC tumours lack three targets that are known to fuel breast cancer growth – estrogen, progesterone and HER2 receptors. This means that the treatment that is often successful in other breast cancer types, is not effective against TNBC” says Professor Scott.

Professor Scott has been working with Professor Roger Daly from Monash University and Dr Ingrid Burvenich from the ONJCRI to develop a novel approach called targeted antibody therapy, to convert estrogen insensitive tumours, like TNBCs, into tumours that have the estrogen receptor, ultimately making them responsive to readily available and effective hormone therapy.

“This project will investigate how effective an antibody called 6B3 is at treating TNBC. In mouse models, our team has shown that the 6B3 antibody can restore the expression of estrogen receptors to the tumour, hence making the cancer sensitive to anti-estrogen therapy,” says Professor Scott.

In addition to this, they will use an imaging technique, PET/MRI to assess the response of cancer cells to 6B3 and determine the best timing for combination with anti-estrogen therapy.

“We would ultimately like to see this antibody targeting moved into a clinical trial over the coming years. If successful, this could make a significant impact to those patients diagnosed with TNBC’s and offer a new novel therapy that could improve patient outcomes,” he says.

“We are extremely grateful to the NBCF for their generous support of this project.”


Transforming rogue immune cells to combat ovarian cancer

Dr Ashleigh Poh, a postdoctoral researcher in the ONJCRI’s Cancer and Inflammation Laboratory has recently secured funding to investigate how rogue immune cells that normally allow cancer to survive can be transformed to fight ovarian cancer.

In Australia over 1700 women are diagnosed with ovarian cancer every year. That’s more than 4 per day. There is no early detection and the five-year survival rate for ovarian cancer has not improved in 40 years.

Dr Ashleigh Poh and her colleagues are working on changing that after sharing in $550,000 from the Ovarian Cancer Research Foundation (OCRF) to continue their work in fighting the disease.

This World Ovarian Cancer Day marks a 14-year partnership between the OCRF and Australian fashion brand Witchery. The campaign, known as ‘White Shirt Day,’ encourages Australian’s to buy a white shirt to support ovarian cancer research, with 100 per cent of proceeds going to the OCRF to fund projects like Ashleigh’s.

“Our research is trying to develop more effective therapies for high grade serous ovarian cancer, which is the most common and most aggressive type of ovarian cancer. Most women who are diagnosed with high grade serous ovarian cancer respond very poorly or not at all to existing drugs and therapies,” says Dr Poh.

The project which is co-led by Professor Matthias Ernst, Director of the ONJCRI and Dr Liz Christie from the Peter McCallum Cancer Centre focuses on targeting a protein known as HCK. HCK is found in a type of immune cell known as a macrophage.

“Under normal situations, macrophages play an important role in immunity against disease, as well as clearing dead cells and debris. However, macrophages can also be ‘corrupted’ or ‘hijacked’ by cancer cells to help tumors grow and remain undetected by the immune system.”

The research team has shown macrophages that have more HCK activity are better at supporting tumour growth and spread. In contrast, drugs that stop HCK activity in macrophages are able to slow the growth and spread of many different tumor types in pre-clinical models, including high-grade serous ovarian cancer.

“This suggests that targeting HCK in combination with existing therapies could potentially improve treatment outcomes across a broad range of cancers including ovarian cancer.”

The work undertaken at the ONJCRI has the potential to help thousands of women around the world.

“Our research aims to develop better treatment options for ovarian cancer patients, with the goal of extending their lives and giving them more time with their family instead of being in and out of hospital. We are grateful to the Ovarian Cancer Research Foundation and the Witchery White Shirt Campaign for their generous support of our research.”


Tissue and Tumour Immunity Laboratory

Tissue and Tumour Immunity Laboratory

Dr Ajithkumar Vasanthakumar and Prof John Mariadason

Exploiting the metabolic dependence of tumour cells for immunotherapy

The immune system plays a key role in recognising and eliminating tumours. Tumour cells however have evolved to employ multiple mechanisms to evade immune attack. Given their high energetic demand, tumour cells rapidly and efficiently use energy sources such as glucose from the tumour microenvironment (TME) making it unavailable for immune cells. Glucose catabolism by tumour cells also leads to the accumulation of intermediates such as lactic acid, which makes the TME hostile for immune cells. Tumour killing immune cells become dysfunctional in a lactic acid rich TME and fail to respond to immune checkpoint blockade therapy. Tumour cells are widely believed to rely on glycolysis for ATP production. However, glucose is the sole energy input for this metabolic pathway. Kreb’s or TCA cycle on the other hand can utilise glutamine, fatty acids and proteins as energy source to produce ATP to power the growth of tumour cells.

We propose to perturb TCA cycle to make tumours fragile and susceptible to immunotherapy. To this end, we will ablate succinate dehydrogense (SDH) enzyme in murine colon tumours using CRISPR technology. This enzyme catalyses the conversion of fumarate to succinate and ablation of SDH will lead to the accumulation of succinate within tumour cells as well as the TME. Broadly, we will investigate how the metabolite succinate directly impacts tumour growth and the influence of succinate on immune cells in the TME. Succinate is known to induce ROS and promote angiogenesis. While counterintuitive, we believe angiogenesis will facilitate recruitment of immune cells to the TME. To unequivocally understand the impact of succinate on immune cells, in particular T cells, will employ SUCNR1 (succinate receptor) deficient mouse models. Furthermore, we will combine SDH inhibition with immune checkpoint blockade to assess the therapeutic benefits of succinate on cancer immunotherapy.

This project will utilize cutting-edge molecular techniques such as CRISPR, RNAseq and ATACseq, multi-parameter flow cytometry, Immunohistochemistry and novel transgenic mouse models.

Basic training in immunology or cancer biology (Honours or Masters minimum) will be required.


Bioinformatics and Cancer Genomics Laboratory

Bioinformatics and Cancer Genomics Laboratory

Prof Wei Shi and Prof Axel Kallies (Peter Doherty Institute)

Reconstructing Gene Regulatory Networks of Lymphopoiesis Using Multi-Omics Data Integration

The adaptive immune response is coordinated by a complex network of two cell lineages, T and B lymphocytes, generated from hematopoietic stem cells through multiple progenitor stages. Lymphopoiesis is the process of lymphocytes differentiation, which is controlled by harmonised transcription of thousands of genes through a complex Gene Regulatory Network (GRN), developing a high degree of phenotypic and functional plasticity in immune cells. Although many genes have been discovered to play a role in an adaptive immune response, the GRN underpinning this important process is poorly understood. In particular, it is unclear how the GRN regulating immune responses is disrupted in cancers such as breast cancer.

Over the last decade, advancements in genomics technologies and generating large amounts of omics data have shown a great promise in dissecting the complexity of lymphopoiesis. In parallel, there has been a growth of online databases, computational methodologies, and tools to explore multimodal data sets and integrate these multi-omics data acquisition to infer the underlying GRN. This study will utilise both public and in-house omics data, including RNA sequencing data, transcription factor chromatin immunoprecipitation followed by sequencing (ChIP-seq) data and assay for transposase-accessible chromatin with sequencing (ATAC-seq) data, to construct GRNs to unveil the molecular mechanisms underlying differentiation of B and T cells.

To construct GRNs, we will start by searching gene that co-express with major transcription factors involved in lymphopoiesis regulation. The interaction between these transcription factors and their co-expressed genes will be validated by ChIP-seq data. The association between transcription factors and chromatin accessibility will be tested by ATAC-seq data. The constructed GRNs will expand our understanding of underlying signalling and transcriptional regulation in lymphopoiesis.

We will then investigate how the expression profile of GRN is altered in breast cancer and understand the differences in expression profile changes in primary and metastatic breast cancer. We will also explore the possibility of using GRN as a tool to predict the prognosis of breast cancer patients.


Molecular Immunology Laboratory

Molecular Immunology Laboratory

Dr Conor Kearney

Systematic identification of novel targets to improve immunotherapies for colorectal cancer.

Immunotherapy has revolutionized the treatment of cancer, with checkpoint blockade therapy showing remarkable efficacy in several cancer subtypes, particularly melanoma. Despite this success, the majority of patients do not respond, for reasons that are not well defined, or acquire resistance after treatment. Furthermore, immunotherapies have proven to be relatively ineffective against some cancer types, including colorectal cancer.  Thus, there is an unmet need to unveil novel approaches to boost the response rate and prolong the extent of the benefit in colorectal cancers­­­, among other cancer types. Similarly, despite the success of adoptive cellular therapy (ACT) in the context of haematological malignancies, response rates against solid cancers is poor, likely due to tumor-associated immunosuppression and subsequent T cell dysfunction/exhaustion. Indeed, it is becoming clear that the failure of T cells to elicit a successful and long-term anti-tumor immune response is controlled by transcriptional, epigenetic and post-translational modifications, however, our current understanding of the molecules involved in these processes is poorly understood. Thus, there is urgent need for a systematic and high-throughput approach to identify novel immunotherapy targets in this regard.

We hypothesise that unidentified genes or proteins in T cells can be targeted genetically or pharmacologically to improve T cell-mediated anti-tumor immunity in colorectal cancer. 

This project will use a high throughput screening approach involving cutting-edge technology including in vitro and in vivo CRISPR/Cas9 genetic screens, the development of novel, high throughput drug screening platforms and single-cell sequencing technology to identify novel targets to improve T-cell mediated anti-tumor immunity in colorectal cancer.

Some experience in molecular biology techniques,  computational biology and/or experimentation involving mice would be beneficial.


Professor Jonathan Cebon awarded 2021 AMRF Distinguished Scientist Award

Professor Jonathan Cebon, former Head of ONJCRI’s Cancer Immunobiology Program has been awarded with the 2021 Austin Medical Research Foundation (AMRF) Distinguished Scientist Award.

The award recognises a prominent researcher who has made a significant contribution to Health Research, fostered young people into research and contributed to the research community at Austin Health. The Austin Medical Research Foundation (AMRF) supports more than 800 researchers in hospital departments, three University of Melbourne departments and four independent research institutes at the vibrant Austin precinct.

Jonathan is a worthy recipient, his impressive career spans 30 years at Austin Health alone. He played an integral role in conceptualising and ultimately bringing to life the vision to establish the Olivia Newton-John Cancer Centre and the Olivia Newton-John Cancer Research Institute as closely partnered organisations. Since then, his expertise and leadership as a physician-scientist have been instrumental in establishing the Austin as an Australian leader in translational research and cancer clinical trials.

Jonathan is the immediate past Medical Director of Cancer Services at the ONJ Centre and ONJCRI and Director of the Ludwig Institute. He is a Professor in Medicine at La Trobe and Melbourne Universities and a Fellow of the Royal Australasian College of Physicians.

“It is an honour and privilege to be acknowledged in this way. The Austin has been such a large part of my career; after first joining the campus as a medical student I then returned in 1992 to take up the position as the Head of Oncology at the then Ludwig Institute. I have spent the past 30 years in cancer research at the Austin and so it is wonderful to be recognised for this contribution.” Said Jonathan.

Jonathan is not only an extraordinary physician-scientist, but he is an outstanding leader and mentor for young researchers. He dedicates much of his time to mentoring postgraduate research students, postdoctoral researchers, Clinical Research Fellows, and Oncology Advanced Trainees, supervising over 21 research higher-degree students during his time at ONJCRI and supporting the careers of countless notable leaders in medical oncology and cancer research, many of whom have gone on to establish their own international and/or national standing.

“There are many important things that constitute successful and enduring research, one of them is collaboration and the other is continuity. When people move on, it is important that research continues and that there are opportunities to build on past achievements, that’s why I think it is so important to support the careers of those coming through.

The work should never be about the individual researcher, it should always be focused on the success of the endeavor.”

There is no doubt that Jonathan’s incredible work and career will continue to impact patients, peers, and young clinician scientists over the coming years.


Colour Coding Cancer

As Head of the Tumour Progression and Heterogeneity Laboratory at the Olivia Newton John Research Institute, Dr Delphine Marino hopes to achieve two things: Finding more effective treatments for breast cancer and supporting the next generation of young female researchers.

It was 2008 when Dr Delphine Merino packed her bags and headed to Australia to start her postdoc.  It was an exciting time for the young researcher who had just finished her PhD at the University of Burgundy in France.

“The time has gone really fast. I was always so fascinated by the biology of cells. Why some cells become malignant and start to form a tumour. So, after finishing University I decided on a PhD in Cancer Research. I came out to Australia for my first postdoc, then decided to stay for a second and here I am 14 years later.”

Not all cancer cells are equal

Delphine’s research is focused on understanding the fate of cancer cells. We know that while some cells respond well to treatment, other cells don’t and may spread to different areas of the body. By understanding why cancer cells vary and how different types of cells behave, we hope to prevent its recurrence, or propose better treatments if the disease returns, giving hope to the millions of women currently going through breast cancer treatment.

“Our research looks at the molecular properties of individual tumours, to understand why some cells are likely to be resistant to treatment and how we might be able to treat them.”

 “We are really trying to understand cells on an individual level to identify the different types of cells that make up a breast tumour. From here we can work out how that tumour might respond to different treatment options, if cancer cells will survive or not survive, which we hope will translate into better treatment options for patients.”

In 2021, Delphine’s team and colleagues published a significant study in Science Advances. The research, funded by the National Breast Cancer Foundation, Komen, Cancer Australia, Cancer Council Victoria and Love Your Sister visualised cancer cells from triple negative breast cancer tumours.

“We used proteins derived from jellyfish and sea anemones to give colours to cancer cells within a tumour. Different cancer cells were allocated different colours so we could tell them apart, and then using microscopes we could study their behaviour.”

“We then treated the cells with two different drugs and were able to clearly see what types of cells were responding and what weren’t, but also, how the cells interacted with each other. We found that there’s complex relationships between cells in a tumor, they may influence each other.”

 “Understanding how the cells behave could help us design better combination therapies for patients. For instance, say a specific drug is working well on some cells but other cells escape and the disease returns. With this strategy, we can better understand what treatment the cells that are escaping might respond to, meaning we can propose efficient treatments to treat resistant cells.”

 “We are now continuing this work using different models and different drugs with the aim of finding better and more bespoke treatments for patients.”

“Tailored treatments for patients are what we are all moving towards. Being able to have someone diagnosed with breast cancer and instantly knowing what treatment will be the most effective is the ultimate goal.”

 

 The global impact on women

In 2020, there were 2.3 million people diagnosed with breast cancer around the globe and over 685,000 deaths. Every 60 seconds someone dies from breast cancer and 99% of those deaths are women.

Delphine talks passionately about how breast cancer research has changed over the years, transforming the way we treat cancer and improving survival rates and quality of life for women and their families.

 “When someone is diagnosed with cancer, we sometimes forget what impact it has on other areas of their health and wellbeing. It might affect fertility or lead to other health issues, so it can have multiple implications, that’s something we really need to change.”

  

Women supporting women

 In 2017, Delphine took up the position of Laboratory Head of the Tumour Progression and Heterogeneity Laboratory at ONJCRI. Her experience has been a positive one, but she admits that while there are high numbers of women in early researcher roles, the numbers start to drop in more senior positions.

“I think there are several challenges. Finding the right work-life balance can be one of them, especially for women with caring responsibilities.”

 “It’s also quite competitive to secure senior roles, although there is an ongoing push to change the mindsets. Having more role models for younger researchers to look up may contribute to achieve this.”

 Delphine stresses that role models and mentors are crucial for changing things for the next generation of female scientists and she hopes that she can play a role in that.

 

Looking to the future

 International efforts in cancer research have the ability to improve the lives of millions of women around the world and Delphine is confident that progress is being made.

“Things are moving really fast in this space so hopefully it won’t be too far away.”


Looking To The Past To Find Answers For The Future

“I know from personal experience how destructive cancer can be for both patients and their families,” says Elnaz Tavancheh, one of ONJCRI’s talented PhD students and winner of the 2020 Ronnie Goldberg scholarship.

The loss of two grandparents to cancer is what inspired Elnaz to pursue a career in cancer research. Arriving from her native Iran in 2014, her research sees her turning to historical tumour and blood samples to make a difference to those diagnosed with Stage III melanomas.

She is using an archival dataset from Melanoma Research Victoria, at the Victorian Comprehensive Cancer Centre, to identify molecular and immunological markers in melanomas to help improve the prediction of relapses.

“From the dataset I have identified 100 patients whose archival tumour and blood donations are suitable for study. The samples are around 10 years old which means we know each person’s outcome. Without their selfless donations, we couldn’t conduct this research, so I’m very grateful to them,” says Elnaz.

Melanoma is a type of skin cancer that develops in skin cells called melanocytes and usually occurs on the parts of the body that have been overexposed to the sun. Australia has the world’s highest incidence of melanoma.

Elnaz’s research focuses on patients with Stage III melanoma who have received treatment but where the risk of future relapse remains. Currently, oncologists use a variety of measurements like tumour thickness to predict a patient’s risk of relapse, but for many patients this is not very accurate.

“Stage III melanoma has huge potential for successful intervention and treatment in a clinical setting if we can better predict which patients are going to relapse,” says Elnaz, who is completing her PhD under the supervision of Tumour Immunology Laboratory Head Associate Professor Andreas Behren and postdoctoral research fellow Dr Jessica Duarte.

“What we have discovered so far in cancer research is only the tip of the iceberg — I picked this career to make a difference for people with cancer and to contribute to new and better treatments and I feel like I’m achieving that.

“I love what I’m doing. My supervisors have a huge amount of knowledge. They’re supportive, but give me the freedom to think independently, make decisions and push beyond my limits,” she says.


A new way to understand cancer

When a team of international researchers made headlines around the world after determining the entire human genome, the news caught the attention of then Dr Wei Shi.

It was 2003 and Wei had just arrived in Melbourne from his native China to take up a postdoctoral research fellowship at Deakin University’s School of Information Technology.

“This important milestone gave birth to the field of bioinformatics. At the time I was simply fascinated by this achievement and made the decision to switch my career from computer science to become part of this exciting new discipline called bioinformatics,” says Wei.

Bioinformatics combines biology, computer science, mathematics and statistics to develop methods and software tools for understanding complex biological data.

Wei worked for nine years in Professor Gordon Smyth’s Bioinformatics and Cancer Genomics Lab at the Walter and Eliza Hall Institute of Medical Research (WEHI), where he was promoted to Lab Head in 2016.

In April 2020, Wei was recruited to ONJCRI where he established the Institute’s first Bioinformatics and Cancer Genomics Lab. Since coming on board, Wei has made a huge impact on ONJCRI research by contributing his bioinformatics expertise to many research projects in collaboration with most of the labs at ONJCRI. These projects investigate multiple different cancer types such as gastrointestinal cancer, breast cancer and brain cancer.

Wei’s work has been cited in more than 22,000 studies, and he was named on the Web of Science Highly Cited Researcher list in 2018, 2020 and 2021. This award recognises the world’s most influential researchers and illustrates the multidisciplinary relevance of his work.

Wei’s work on developing and improving bioinformatic methodologies benefits research has a large impact far beyond cancer research. The paper he and his colleague Dr Yang Liao published in NAR Genomics and Bioinformatics in 2020 is a case in point. The paper demonstrates that a time-consuming process called ‘Read Trimming’ can be excluded from the RNA-sequencing process without having a negative impact on results.

“Instead of convincing people to do something, I want to convince them not to do something,” explains Wei. “Our work in this 2020 paper shows that if researchers exclude the computationally intensive ‘Read Trimming’ from their sequence analysis process, they can reduce analysis time by 40 per cent yet gain similar results. Our method is faster and easier.”

Wei’s expertise has led to many collaborations here at ONJCRI and with researchers around Australia and the world.

“I’m passionate about bioinformatics research. I’m really excited every day by what we’re doing — developing new methods that will make a difference to basic science and the way that it impacts on clinical care.”