2017 funding recipients

Novel immunotherapy approach for rescuing inadequate responses and resistance to treatment for patients with multiple myeloma

Resistance to therapy is the main barrier to cure for the blood cancer multiple myeloma. Immune therapies potentially overcome resistance, and provides prospect of durable control if not cure. This study evaluates the effectiveness of rescuing poor responders/ reversing resistance to lenalidomide (an established immunomodulatory drug for multiple myeloma), by blocking a protein on myeloma cells called 'programme-death-ligand-1' (PDL-1) which dampens immune function. This effectively lifts a major barrier to immune activity and was proven highly effective in the laboratory. We will trial this in the clinic  and  incorporate immune and genetic tests for markers that can predict response.

Sequential functional imaging for breast cancer – Tumour characterisation, therapy optimisation and tumour response monitoring

Patients with triple negative and HER2+ (human epidermal growth factor receptor 2 positive) breast cancers are currently faced with demanding treatment regimens comprising neo-adjuvant chemotherapy, surgery and radiation therapy. These treatments are associated with significant toxicity and resource implications. We will incorporate novel imaging technologies, to study breast cancers prior to and following chemotherapy. We will assess and compare tumours on both modalities with pathological samples and provide clinicians with highly accurate functional, volumetric and spatial information and we will investigate blood markers for the prediction of metastasis. Ultimately, these studies will facilitate individualised treatment strategies, including de-escalation of surgery and radiation therapy.

Application of modern image processing and machine learning techniques for individualised management and optimised use of targeted therapy in neuroendocrine cancer

This fellowship will focus on improving the treatment of neuroendocrine cancer with targeted radionuclide agents. we will employ machine learning approaches to identify predicting factors - either alone or in tandem - which determine likelihood of response or potential to personalise treatment to each individual. We aim to automate this process by applying modern deep learning image analysis techniques; allowing us to analyse information from several hundred patients in a manner that wasn’t previously feasible. The work will directly inform patient management and yield technical developments that can be adapted to the diagnosis and treatment of other cancer types.

Immunostaging for melanoma to accurately predict the risk of relapse

Melanoma that has not spread to distant organs is usually treated with surgery followed by a watch-and-wait approach. However, the risk that the cancer reoccurs after surgery ranges from 10 per cent - over 50 per cent, often spreading to other places in the body (metastasis).  Currently, there are no good markers to accurately predict who relapses. The immune system is important in controlling cancer and relapse, and therefore we propose to use specific immune system measurements to identify those at high risk. Combining these with clinical observations ('immunostaging'), will better determine who is at high risk and should be sent for additional intervention.

Targeting inflammation to prevent breast cancer

Changes in childbearing today mean women are bearing fewer children and at older ages. This is driving an increase in breast cancer incidence as young childbearing (parity) protects against breast cancer.  Our parity studies in studies mice revealed a fibroblast secreted anti-inflammatory protein is highly expressed in parous protected breasts. Its highly expressed in normal breast and lost in breast cancer. We used it to predict the outcome of early stage patients and showed it was safe and effective at inhibiting breast cancer in mice. Here we will determine the best way to develop it into a breast cancer therapy.

Targeting cell metabolism to improve the treatment of triple-negative breast cancer

Chemotherapy is the mainstay of treatment for triple-negative breast cancer, an aggressive subtype of breast cancer. Unfortunately, the majority of triple-negative breast cancer patients do not respond adequately to chemotherapy and long-term prognosis for these patients is poor. We have identified a mechanism that limits the efficacy of chemotherapy for the treatment of triple-negative breast cancer. In this project, we will establish novel combination therapy strategies to improve survival outcomes for patients diagnosed with triple-negative breast cancer.

Identification of Epigenetic Therapeutic Targets in Malignant Rhabdoid Tumours

Malignant Rhabdoid Tumours represent the most resistant of childhood cancers to current standard therapies and have a dismal outcome. We have recently demonstrated the therapeutic potential of the Histone Deacetylase Inhibitor, Panobinostat, in Malignant Rhabdoid Tumours leading to an investigator-initiated clinical trial. However, broad and subgroup-specific overexpression of distinct subsets of genes suggest that several mechanisms may underlay disease development and progression for which a single agent therapeutic approach might not be effective. This proposal will identify druggable targets in Malignant Rhabdoid Tumours that synergise with Panobinostat to provide a more efficacious and durable tumour response, leading to improved patient outcome.

Incorporating the Victoria-USA Cancer Fellowship Exchange Program

Discovering new therapies for rare, highly aggressive subtypes of prostate cancer through genome profiling

There is substantial variation in how well prostate cancer patients respond to the standard therapies of androgen deprivation and chemotherapy. However, prostate cancer still treated in a ‘one size fits all’ fashion. Poorly responding tumours are often enriched in particularly aggressive cell types. Tumours containing such highly malignant cells will be grown in mice, to mimic the course of patient treatment. We will use DNA sequencing to study in great molecular detail how these tumours change in response to therapy. This work will show how therapy resistance occurs, help identify resistant tumours and develop new first-line therapies for at-risk patients.

Advancing the therapeutic targeting of the pro-survival BCL-2 family protein, MCL-1, using humanised haematopoietic cancer models and patient samples and a novel BH3-mimetic drug

Blood cancer is the third biggest cause of cancer death in Australia. Therefore there is a desperate need for improved therapies. A new class of drug, called BH3-mimetic, has recently been developed. These drugs kill cancer cells by binding to cellular proteins that control if a cell lives or dies. Here a new BH3-mimetic drug that targets a survival protein called MCL-1 will be investigated using novel pre-clinical blood cancer models and blood samples from leukaemia patients. These studies will facilitate and support the clinical translation of this new cancer therapy.

Improving the clinical use of the anti-cancer agents smac-mimetics

The anti-cancer agents called ‘smac-mimetic’ are currently showing promise in clinical trials. However, many types of cancer will not respond to smac-mimetic alone. I will decipher the mode of action of smac-mimetic to anticipate resistance and side effects. I will determine which cancer types are more likely to respond to smac-mimetic, and test new combination therapies using smac-mimetic. These studies will guide and refine the design of future clinical trials of smac-mimetic.

Novel RNA processing based therapies in haematological malignancies

This proposal will systematically determine how  messenger RNA splicing and export, two coupled steps in the gene expression pathway, are altered in haematological malignancies, identifying potential therapeutic vulnerabilities. This will enable us to develop novel RNA processing based therapies to treat patients with mutations in RNA processing factors.

Targeting dysregulated gene expression in haematological cancers with CDK9 Inhibitors

A new class of drugs called CDK inhibitors have shown promising results in the laboratory and in early clinical studies for patients with blood cancer.  However, many patients eventually get relapsed disease and therefore new treatment strategies are needed. How these drugs work in cancer cells is not completely understood and this project will use new sequencing technologies to investigate how blood cancer cells respond to drugs that target a protein called CDK9. It is expected that this study will identify strategies to enhance the effectiveness of CDK9 inhibitors and improve patient care.

Can genomic profiling help predict who will get a second bowel tumour?

People developing a pre-cancerous polyp in the large bowel are more likely to have a subsequent polyp or bowel cancer develop; currently we cannot accurately tell who will or will not. Using state-of-the-art genomic testing methods offers an opportunity to more accurately discriminate those at low-risk of getting a second polyp/bowel cancer from those at high-risk. Using bio-resources, clinical and 15 years of follow-up data from a large Australian bowel cancer study, we aim to develop a model that incorporates novel genomic profiling to determine a person’s risk of developing cancer of the large bowel after an initial polyp diagnosis.

Next generation targeting of DNA methylation to translate improved outcomes in T-cell lymphoma

Lymphoma is a cancer that develops from either the B-cell or T-cells of the immune system. Unlike B-cell lymphoma, T-cell lymphoma is much harder to treat and often becomes resistant to conventional chemotherapy. We noticed that some of the genes that are mutated in T-cell lymphoma are also seen in a cancer of the bone marrow called 'myelodysplasia'. We will therefore test an exciting new myelodysplasia drug called SGI110 in T-cell lymphoma. This project will help understand how SGI110 works in T-cell lymphoma and progress its clinical translation in this new disease area.

Improving outcome in childhood acute lymphoblastic leukaemia through biology-guided treatment

The project is centered on improving the effectiveness of treatment in children with acute lymphoblastic leukaemia who respond poorly to or relapse following standard-of-care therapy. Many such patients currently die from their leukaemia, despite intensive second-line therapy. We have an increasing capacity to comprehensively characterise the biology of individual leukaemias, particularly through detailed genetic analysis. However, there is still significant uncertainty in many patients on how to optimise treatment using this information. This project focuses on translating biological data to improve treatment precision and effectiveness, particularly with the use of newly developed, targeted drugs.

Benefits of home-based rehabilitation in inoperable lung cancer

Exercise rehabilitation is not part of routine care for people with lung cancer in Australia. In people with breast, prostate and colorectal cancer evidence shows that individuals who are more active have improved quality of life and physical function, better symptom control and longer survival times. This project aims to investigate the benefits of providing home-based physiotherapy exercise with support to manage symptoms to people with lung cancer, during and following treatment other than surgery.

An exploration of cognitive impairment in patients with multiple myeloma to inform effective supportive care

Cognitive impairment is a common side effect of cancer chemotherapy that may last for months or years after treatment. Little is known about cognitive impairment and there are few effective interventions to reduce its impact on peoples’ quality of life. This research focuses on cognitive impairment in patients with multiple myeloma, a disorder of plasma cells that affects approximately 1600 Australians each year. cognitive impairment is known to be a distressing side effect of multiple myeloma treatment. This study aims to describe in detail the onset of cognitive impairment and pilot test an internet-based brain training program to reduce its impact.

Understanding nutrition related symptoms, complications and quality of life in patients with gastrointestinal neuroendocrine tumours

Neuroendocrine tumours of the gastrointestinal tract and their treatment often cause symptoms that impact a patient’s quality of life and nutritional status. Despite improvements in the management of neuroendocrine tumours over the past decade, evidence to inform supportive care interventions and improve patient’s quality of life is lacking. Neuroendocrine tumour patients can experience various symptoms, but Australian evidence on symptom prevalence, severity, management, and patient experience is limited. This research will explore nutrition related symptoms, their impact on patient quality of life and provide evidence to inform nutritional management strategies.

Mapping patterns of care for people with pancreatic cancer: how close are we to the Optimal Care pathway recommendations?

Pancreatic cancer has one of the lowest survival rates of all cancer types, and people with pancreatic cancer can experience a range of symptoms including pain, weight loss, and high rates of anxiety and depression. In order to determine where improvements can be made to patient outcomes, the care pathways of a cohort of Victorian pancreatic cancer patients will be mapped and compared to the consensus-based optimal care pathways. Timely referral to palliative care services is a key component of the optimal care pathway, and has the potential to deliver a range of beneficial patient outcomes.

Understanding patients’ and family members’ clinical trial experiences and perspectives about palliative care’s relevance

Early phase clinical trials are increasingly offered to patients with cancer, and provide a means to access new treatments where the standard cancer treatments have been exhausted. Patients and their families have to balance their hopes for a personal medical benefit with the realities of their disease and the demands of participating in a clinical trial. Understanding how patients and their families make their decisions, how they experience the clinical trial process and think about the access to palliative care is very important, with implications for trial design, the informed consent process, and service delivery of palliative care.

Understanding spiritual views and requirements of caregivers of people living with serious illnesses

It is recommended that palliative care providers explore the 'spiritual requirements' of those affected by serious illnesses, to address existential concerns and spiritual pain. There remains, however, limited data on this topic in Australia. This mixed methods study will involve 100 informal palliative caregivers and aims to understand associations between caregivers’ spiritual well-being, levels of spirituality, spiritual concerns and support received. It will explore how caregivers conceptualise spirituality and their views about spiritual care provision. This study follows near completed research, exploring the above issues in patients with serious illnesses. Findings will inform development of innovative spiritual palliative care approaches.