2023 successful cancer researchers and projects

• Utilise immune cells that are rarely found in the brain
• Have been developed for adults and tested in adult preclinical models
• Have not been designed to complement existing front-line therapies that are proven to work

To address these gaps in knowledge, we identified a novel immunotherapy drug called magrolimab which harnesses immune cells abundant in children’s brains. We pioneered methods to grow and treat tumours in the brains of very young mice, to mirror cancer growing in a child’s brain. Initial investigations prove that the tumours and immune systems are different in child compared to adult models. We tested magrolimab combined with radiation in these mice and it eradicated an aggressive brain cancer called meduloblastoma. In this project, we will determine if the novel treatment is also effective for ependymoma. We are uniquely placed to translate our findings into new international clinical trials that will benefit WA children first.

Hck is only found in macrophages, an immune cell type found in large numbers in triple negative breast cancer. We have previously shown that the most dangerous macrophages are those that invade surrounding organs in the body and encourage cancer cells to follow them. Recently we have shown that active Hck turns on macrophage invasion while inhibition of Hck stops macrophages and accompanying cancer cells from invading.

We aim to firstly develop a clinically-relevant test to identify the patients who have the AAMDC repeat. We will also study the expression of the AAMDC protein in a cohort of more than 200 archived samples from OC patients in WA. We will then correlate the presence of AAMDC repeat and that of the protein, with available clinical data (survival and treatment). The detection of AAMDC should identify the patients that develop treatment resistance.

Secondly, we aim to develop completely new targeted treatments that are specifically for this subset of patients. New treatments should improve the response of OC cells to cisplatin treatment. Our new agents are small versions of AAMDC, called AAMDC-interference peptides (AAMDC-iPEPs). We will test if the peptides kill the OC cells first in cell lines and then next in pre-clinical studies (mouse models).

The purpose of the research is to develop novel targeted treatments for TNBC. We will harness state-of-the-art technologies (named CRISPR) to shut down the key genes that cause cancer spread and treatment-resistance. These genes, named ZEB1, TWIST1, SNAIL and SLUG, work together to activate metastatis and therapy-resistance. They also disable the immune-system from either recognising or killing tumour cells. Aim 1 – we will investigate the molecular changes in the TNBC cells after we treat them with CRISPR. We will study if TNBC cells become sensitive to particular drugs that are either approved for cancer (chemo or immune-based therapies) or in clinical use for other diseases. We will also identify novel drugs, which will be tested in start-of-the-art pre-clinical trials for their ability to kill TNBCs derived from patients. In Aim 2, we propose to systematically deliver the CRISPR treatment in animal models of TNBC. We will study if CRISPR prevents disease spread and sensitises TNBC to chemo and immune-based therapies.

1. RT Prepare program: This program focuses on preparing people for radiotherapy. Little research has been conducted in this area. This team’s work in preparing people diagnosed with breast cancer for radiotherapy is recognised internationally; however, this program needs to be refined for people with other cancers. Receiving radiotherapy for brain cancer or head and neck cancer may cause distress due to the head mask they must wear to stop them moving and side effects they might experience. People receiving radiotherapy for head and neck cancer are at risk of severe skin reactions, dry mouth, oral discomfort, mouth ulcers, infections, difficulty chewing and swallowing, impaired taste and extreme weight loss. People receiving radiotherapy for brain cancer may fear side effects such as headaches, hair loss, nausea, extreme tiredness, hearing loss, skin changes, speech difficulties and seizures. Education and support provided by the radiotherapy team before treatment is likely to reduce their anxiety and help them manage side effects.
   Research methods for this program will include interviews, development and testing of the education packages and a large scale clinical trial. Main outcomes will include anxiety and distress, concerns and knowledge about radiotherapy and how prepared they feel for treatment.
2. Carer’s Education and Support Program: This program focuses on improving carer’s confidence to look after their loved one after a cancer diagnosis and reducing their level of distress. This research focuses on carers of patients diagnosed with brain cancer or head and neck cancer because these groups would benefit most from extra support. If carers are unable to support their loved one, it is likely that the person with cancer may need additional emergency room visits or hospital admissions. During the program a nurse conducts a telephone assessment, visits the carer at home, provides an individualised resource manual and regular telephone follow-up for 12 months. This program is currently being tested in a randomised controlled trial with carers of people with brain cancer. It needs to be adapted and tested for carers of people with head and neck cancer.

Research into these two programs is essential to improve the education and support provided to individuals and their carers following a diagnosis with either brain cancer or head and neck cancer. The team will also determine the cost of providing these programs and the impact they have on overall healthcare costs.

By combining these existing medicines with low-dose radiation therapy, I can determine if

1. this more effectively kills brain cancer than radiation alone (which is the standard treatment today AND
2. If this reduces the side effects of radiation, since the dose is lower. If successful I will move this finding into clinical trials quickly, as this will be the first time a new treatment for brain cancer has been identified in more than 30 years.

After developing a new analytical platform that involves acquisition of large amounts of biological information from thousands of liver cells with unprecedented level of detail, the aim is to identify molecular signatures that can predict liver cancer before it develops.

It is important to predict cancer as early as possible as liver health can be restored before the damage becomes permanent and catastrophic. Early detection will improve survival and quality of life, as seen with other cancer types for which screening programs are in place.

The purpose of this project is to investigate the effects of exercise on blood flow and oxygenation in tumours of men with prostate cancer undergoing radiotherapy. I will first examine if a single exrcise session can improve tumour blood flow and oxygenation. In addition, I will examine long-term effects of exercise training over the course of radiotherapy on tumour blood flow and oxygenation as well as whether exercise can reduce treatment-related side effects such as bladder and bowel symptoms.

The impact of these results, if proven effective, are enormous. Reducing urinary side effects addresses a major issue for prostate cancer patients. Furthermore, by demonstrating the effects of exercise on tumour blood flow and oxygenation, I hope to highlight exercise as a low-cost therapy that can enhance the effectiveness of cancer treatment.

Due to the high rates of relapse and drug resistance seen in chemotherapy, targeted cancer immunotherapies have been developed as alternative treatment options. These therapies boost a patient’s immune system, to help the immune cells find and kill cancer cells. However, though these treatments have worked well in some hard-to-treat cancers (e.g. melanoma), their use in BC has not been as successful. One major reason for this is that BC itself is able to “turn-off” important genes which help the immune system to “see” the cancer. In doing so, the cancer cells can stay hidden and survive.

This project aims to use state-of-the-art gene editing technology to design and test a new target treatment that can reverse this process and “turn-on” the important genes that BC has previously “turned-off”. If successful, the treatment designed as part of this project will help to make BCs more visible to the immune system. Therefore, the patient’s immune system will better be able to “see” the cancer and work in combination with other currently available therapies to improve their rates of success. Furthermore, given other cancer types also “turn-off” the same genes, this treatment is likely to benefit other cancers as well (e.g. pancreatic cancer).

Radiotherapy is given to more than half of all cancer patients and can even cure some cancers. We know that radiotherapy kills cancer cells and stops them multiplying. However, radiotherapy can also boost immune responses to cancer. Combining radiotherapy with immunotherapy could greastly improve treatment responses.This research aims to find the best way to combine radiotherapy and immunotherapy. We have already found a particular combination that can cure 100% of tumours under the skin in mice. Further information may enable radio-immunotherapy be taken into human. This project studies how radiotherapy changes immune cells to help them destroy tumour cells. Testing will also be undertaken on how well radio-immunotherapy treats cancer that has spread. We will also attempt to treat tumours surrounding the lung, mimcking where mesothelioma occurs in humans.This project will use mesothelioma mouse models and a highly precise X-ray machine for irradiations with the goal of providing evidence needed to start clinical testing of radio-immunotherapy for mesothelioma patients. This research will ultimately result in better treatment options and survival for many cancers.

This project will utilize a new approach by employing a specific tool called Epi-CRISPR to switch off the new gene to inhibit the growth of EWS cells. We will also develop a new carrier for Epi-CRISPR to facilitate its clinical application. To achieve these goals, several lab assays and animal models will be used. This project is expected to improve the life expectancy of EWS patients and to make a paradigm shift in the scope of Epi-CRISPR applications in clinical trials that are not exclusive to EWS but extend to other types of cancer

During a patient’s treatment, accurately inspecting these images becomes challenging and potentially misleading e.g., treatment effects (such as inflammation) may appear to look like tumour recurrence on a MRI, which can cause a premature halting of treatment. To be confident, doctors often must implement a “wait and see” approach for conclusive evidence which, with an aggressive cancer like glioblastoma, can be detrimental to a patient’s outcome.

Doctors don’t use the digital data available within medical images, which are made up of hundreds to thousands of numbers. Advancements in computing has opened an additional avenue of research where we believe that artificial intelligence can process this data to inform on a glioblastoma patient’s predicted survival or tumour recurrence. This can act as an additional set of tools for doctors so that they can confidently pivot patient treatment earlier and with more accuracy, which is expected to improve survival.

These approaches will be applied to positron emission tomography (PET) combined with a radioactive tracer with demonstrated beneficial properties in glioma imaging called O-(2[18F]-fluorethyl)-L-tyrosine (FET). In parallel, we will also investigate the use of an automated artificial intelligence pipeline applied to a relatively new MRI sequence using amide proton transfer (APT), which has also shown promising predictive power for patient survival.

This information will be used to study four priority areas: What cell types are present in each tumour? ; Which drugs might kill these cancer cells, what fraction of cancer cells are likely to be resistant and why are some cancers resistant?; What changes between the cancer cells in a primary site when they move to a metastatic site?; and can new biomarkers be identified for early cancer detection and can cancer cells be detected in the blood?

New treatments are urgently needed to overcome drug resistance. One of the most exciting clinical development in recent years is the advent of immunotherapy. Immunotherapy harnesses the body’s own immune system to fight cancer. This treatment is already used for some advanced cancers such as melanoma, often with dramatic results. However, so far GIST has not been considered for immunotherapy. New research published in 2020 indicates that some GIST patients (approximately 50%) spontaneously display lymph node like structures which promote immune cell trafficking and indicate better overall survival.

This research proposal will build on these findings using our expertise in the field and incorporate a unique animal model to test how these lymph nodes can be induced to optimize immunotherapy. For this aim human cancers will be grown in a mouse which harbours a human immune system; this is currently the best model system for studying immunotherapy effects.

We will also collect clinical GIST cancer specimen and examine the numbers and characteristics of spontaneous lymph nodes by developing a new detection system. We expect that this will be useful to identify those GIST patients who will benefit from immunotherapy.

Overall, the goal of the project is to provide GIST cancer patients with new immune based treatment options by combining already available drugs, to overcome resistance and prolong survival.

The team recently showed that a clinic-based targeted and supervised exercise and nutrition program was effective in reducing fat mass by ~3kg in these men. The problem is that not all men would have access to such a program, such as those in regional, rural and remote settings, or have the financial ability to pay. Telehealth has emerged as a viable way to deliver health care. The aim of the project is to determine if the program delivered via telehealth is as effective as the supervised clinic-based program for fat weight loss, reducing cardiovascular disease risk, and enhancing physical and mental health in overweight/obese men with prostate cancer.

The study will recruit 104 overweight/obese men with prostate cancer and current or past usage of hormones and randomise them to a telehealth delivered program or the supervised clinic-based program for 6 months and then follow them for an additional 6 months. The clinic-based exercise program, which comprises resistance and aerobic training, with nutritional advice will be the same as that in the pilot study and will be adapted to be delivered by telehealth using the latest technologies such as video chat with remote monitoring.

If the telehealth delivered program is effective, then it can be rolled-out at a low cost to patients, regardless of their financial position or where they live.