Blood Cancer Fund

Dr Kate Vandyke; University of Adelaide

Multiple myeloma (MM) is an incurable haematological cancer that is responsible for an estimated 80,000 deaths each year worldwide. Even with the best available current therapies, almost all MM patients eventually relapse, with only 15 per cent of patients surviving 10 years from diagnosis. Previous studies have identified that those patients that have highly “metastatic” MM tumour cells at diagnosis do particularly poorly, leading to rapid disease progression, relapse after treatment and death.  Identification of the factor(s) involved in the recirculation and dissemination process in MM is therefore key in the development of therapeutic strategies that will prevent overt relapse in these patients.

Through your support, we will investigate why some patients do very poorly after diagnosis (surviving less than two years) and identify tailored treatments for this group. Importantly, our work focuses on the repurposing of existing targeted therapies that have been trialled in other disease settings. This makes translation of the results of these studies to the clinic feasible in the short term, meaning that real improvements in survival outcomes should be rapid for these patients who traditionally have had very poor outcomes.

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Professor Deborah White; SAHMRI

Acute Lymphoblastic Leukaemia (ALL) is the most common childhood cancer and remains the leading cause of non-traumatic death in children. Adolescents and young adults with ALL have poor therapeutic outcomes and most adults will die of their disease.

Genomic analysis has revealed several new, high-risk ALL lesions that may be targetable with rational therapies. This is supported by anecdotal reports of significantly improved outcomes, but to date both druggable target identification and patient access to these therapies is limited. Importantly, patients with high risk genomic lesions are currently not recognised at diagnosis and are only screened for genomic lesions when they relapse or fail to respond to chemotherapy; for many patients this is too late. They then undergo high dose toxic chemotherapy and/or transplantation, both associated with life-long risk of co-morbidities and second malignancy. Newer immune based therapies are emerging, but we currently don’t know which patients will benefit from these approaches.

Through your support we will investigate Precision Medicine, integrating genomics, metagenomics, bioinformatics and functional analyses, to provide diagnostic screening and therapeutic triage models that are readily accessible and importantly, will transform treatment and outcomes for our most vulnerable ALL patients. Our group is ideally placed to bring real change for ALL patients to ensure they receive the right therapeutic approach early, improving the clinical outcomes for patients with ALL, which can then extend to other cancers.

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Dr Tessa Gargett; University of South Australia

Immunotherapy stimulates the immune system to attack and kill tumours. The immune system contains cells that have the unique capacity to destroy cancer, however tumours often develop ways to turn off these cells and escape destruction. The most successful new immunotherapies (trade names Keytruda, Opdivo and Yervoy) work by blocking the tumour’s method of escaping and allowing the immune system to kill cancerous cells.

These therapies can be highly effective and around 40% of patients with melanoma will respond to therapy, with some patients even achieving a complete response where their tumours are eradicated. However, despite these promising results, approximately 60% of melanoma patients do not respond. Other forms of solid cancers like brain cancer also fail to respond, and so these patients are completely missing out on these breakthrough treatments.

Through the support of Cancer Council’s Beat Cancer Project, we plan to extend the promise of immunotherapy to all patients. We’re testing brand new immune-based therapies specifically designed to boost the immune system in solid cancer patients. We have one clinical trial currently running at the Royal Adelaide Hospital which tests a personalised cell therapy in patients with melanoma. We will soon commence two new cell therapy clinical trials in patients with brain cancer. This project will help develop these trials and also follow patients receiving the new treatment to see how they respond, with the hope that the results can help inform treatments for all patients diagnosed with solid tumours.

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Professor Tim Hughes; University of Adelaide

Just over a decade ago, Chronic Myeloid Leukaemia (CML) was still considered a death sentence. This research has pioneered the use of tyrosine kinase inhibitors (TKIs) to treat a range of cancers including CML, which was once known as one of the most devastating forms of blood cancer. Through the use of TKIs and research into individualised therapies, we have seen significant breakthroughs, with some CML patients even achieving treatment-free cancer remission. This in itself is a remarkable achievement considering that previously, only one in six CML patients survived eight years after their diagnosis.

Thanks to Cancer Council’s Beat Cancer Project, our team has received ongoing funding to support our work since 2013. We’re currently leading a global trial of a promising new therapy for CML, with results to be released later this year. Funding from the Cancer Council’s Beat Cancer Project has enabled our team to lead this and other research projects in South Australia which will ultimately change lives.

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Dr Daniel Thomas; The University of Adelaide

Cancer is primarily a disorder of cell growth which ultimately kills the patient. Historically, the study of cancer growth pathways have focused on a rare, non-representative cell lines and the results have not translated into effective clinical therapy. Worldwide, very few comprehensive metabolism studies have been performed with primary cancer samples from patients.

South Australia stands poised to be a world leader in this new and vital area of research for three critical reasons:-

• (i) We have some of the best clinically annotated tissue banks in Australia and an outstanding track record in clinical trials for targeted therapies, beginning with blood cancers;
• (ii) world class investment in mass spectrometry
  expertise and,
• (iii) cancer researchers in South Australia have engineered sophisticated in vivo models of cancer using primary cells, including humanized ossicles, multiple myeloma metastasis models, colon organoids and in situ brain cancer models. We are thus well-positioned to begin to measure primary cancer cell growth in pre-clinical models and clinical trial patients receiving targeted therapy.

Recently, we and others have used new non-radioactive isotope technology to label and track nutrients inside cancer cells (see attachment in CIA letter of Support). This has revolutionized the study of cancer growth. We have the opportunity to lease cutting edge equipment, software, standards and isotopes to track how cancer cells metabolise any nutrient or any small molecule from a world class company that has developed dedicated components and analytical methods. The package includes training and financial support of future PhD students and a dedicated operator to work leading cancer researchers in SA.

Our exciting results published in leading journals have shown that primary human cancer cells metabolise nutrients in many different ways and struggle to adapt to sudden changes in metabolism, unlike healthy normal cells.

We have developed new small molecules that can block cancer cell metabolism at key branch points in the cell. Blocking cell growth pathways represent a unique opportunity to target cancer without chemotherapy or radiotherapy. The equipment and skills arising from this infrastructure grant will establish our centre in Adelaide as a world leader in primary cell tissue banking and metabolic flux analysis. Marten Snel is a world leader in applied mass spectrometry and lipidomic imaging, leads an outstanding core facility at SAHMRI and will assist in training PhD and post-doctoral researchers together with leading cancer investigators.

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Professor Caroline Miller and Professor David Roder; SAHMRI and University of South Australia

The South Australia Clinical Cancer Registry (SACCR) consists of four hospital-based clinical cancer registries and a central coordinating unit. The clinical registries provide information on cancer stage, grade, differentiation, treatments (surgery, radiotherapy, chemotherapy etc.), prognostic indicators, patient outcomes and other key indicators of quality cancer care that are needed to complement population incidence registries.

Data is limited to those who are treated at participating hospitals Flinders Medical Centre, The Queen Elizabeth Hospital, Lyell McEwin Health Service and the Royal Adelaide Hospital. Clinical registries provide clinicians and service planners with appropriate insight into current cancer trends and the impacts of changes to clinical practice and models of care on outcomes. There are over 300 data items potentially collected as defined by the South Australian minimum data set.

With the funding received through Cancer Council’s Beat Cancer Project and other revenues, we will be able to continue collecting South Australian cancer-related data, enabling effective public health interventions and cancer incidence monitoring through sharing this data with clinicians and service planners.

Professor Ross McKinnon; Flinders University

My wife succumbed to breast cancer when aged 40. During the 15 months she lived with cancer, she experienced major drug toxicities and many ineffective drug treatments, many of which could have been avoided with better utilisation of biological markers and a higher level of pharmaceutical care. Her experience motivated me to optimise drug treatments for future generations, ensuring that others don’t have to experience what she went through.

The ongoing support of Cancer Council’s Beat Cancer Project will help us develop better and more effective drugs to treat cancer. We are researching across three main areas: using Indigenous knowledge and Australia’s remarkable marine biodiversity to identify new compounds with therapeutic potential in cancer and related conditions; using sophisticated statistical methods to determine if such biomarkers (biological indicators of disease) will be useful decision tools in cancer therapy; and studying the mechanisms by which cancer drugs are metabolised to determine ways to optimise drug strategies.

My message to donors is that drug discovery is difficult and challenging, but through a continuity of funding, we are getting closer to drug breakthroughs every day.

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Professor David Roder; University of South Australia

The primary aim of our unit is to develop more efficient and cost-effective services, especially related to cancer screening and treatment. With cancer impacting one in two Australians by the time they turn 85, our work is to benefit the whole Australian population, with the funding we receive from Cancer Council SA greatly increasing the reach of our work.

Through your support, our next step is to assist in the implementation of evidence-based health policies and evaluate their effectiveness. This work is ongoing, with a major emphasis on evaluating and improving outcomes of services for Aboriginal people. We are also working on assessing side effects of cancer therapies in order to improve the quality of life for those who survive their cancer diagnosis and looking at service evaluation and policy development for breast and cervical screening and cancer treatment services.

The South Australian Cancer Research Biobank (SACRB) is a statewide research facility that collects blood, bone marrow, and other tissues from cancer patients, and stores them for future use in research.

Biomedical researchers in South Australia can apply to the biobank for the samples needed for their research projects.

Dr Nicola Poplawski; CALHN

When a client is referred to the AGU we collect and record family history information. The data is collated in KinTrak and clinical staff use the information to determine which cancer genes will be tested and provide an assessment of personal cancer risk.

If a genetic error is identified in a cancer gene, clinical staff use the information to manage risk notification and predictive genetic testing for current and future generations of the family; ensure relatives who do not have the genetic error avoid unnecessary cancer surveillance and provide relatives who do have the genetic error with gene specific risk management advice that lowers their cancer risk (prevention and risk reduction) and enhances detection of early stage cancer (surveillance).

Where ethically approved, research staff use the information to identify individuals/families who are eligible for recruitment to familial cancer research projects; identify individuals/families who are eligible for research or translational genetic testing and contribute data to local, national and international research initiatives relevant to familial cancer

Through support from Cancer Council’s Beat Cancer Project we will be able to employ a data officer to take over these tasks and also support and contribute to AGU research activity, freeing clinical staff for research activities.

Associate Professor Andrew Roland; Flinders University

The project undertaken through this Mid-Career Research Fellowship will address an important impasse that currently prevents cancer patients from achieving the maximum benefit from the use of a key class of anti-cancer medicines. Observational studies consistently show that the benefit achieved by using the class of anti-cancer drugs called kinase inhibitors (KIs) can be dramatically improved, in cases even doubled, by getting the right dose for each patient. Importantly, however, the evidence that comes from these studies is not strong enough to inform practice, and because of this potential value of ‘precision dosing’ for these drugs continues to go unrealised. I have already engaged, and secured funding from, leading local and international academic and pharmaceutical industry partners and established a novel, readily actionable strategy (‘ADMExosomes’) to track the impact of variability in drug exposure on the effectiveness and tolerability of a drug.

Through this fellowship I will evaluate the capacity of this strategy to efficiently generate practice changing evidence defining the value of precision dosing for KIs. Importantly, I have also already established a framework through engagement with my existing network of clinical, consumer and industry collaborators to translate the findings, where appropriate, into actionable ‘companion diagnostics’ that maximise KI effectiveness and tolerability in real world cancer patients.

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Cancer Council SA’s Behavioural Research Team is based at our offices at Greenhill Road. Through your support, the team conducts monitoring, applied research and evaluation to inform the development of Cancer Council SA’s cancer control programs and services. The Behavioural Research Team works closely with the Cancer Council SA Postdoctoral Fellow (Cancer Support) who is jointly based at the Flinders Centre for Innovation in Cancer. Together with two new postgraduate research students from Flinders University, they are interested in people’s knowledge, attitude, behaviours and the decisions individuals make that may lead to healthy or unhealthy behaviours in the area of cancer control, as well as research into the psychosocial impact of cancer on those directly and indirectly affected by cancer.

Dr Ilaria Stefania Pagani; SAHMRI

Chronic myeloid leukaemia (CML) can be controlled by tyrosine kinase inhibitors (TKIs), but about 20 per cent of patients are resistant to first-line therapy and some of them develop fatal blast crisis. Even when treatment is effective most patients need to take TKIs lifelong. This means that there are now thousands of Australians dependent on TKIs, with resulting side effects and costs. Persistent disease indicates the failure of TKIs to target the CML stem cells. Stem cells have a unique metabolic profile characterised by energy production through the mitochondria. Giving a TKI together with a drug that blocks stem cell metabolism could eradicate persistent cells and contribute to an eventual cure. Mitochondria possess their independent DNA (mtDNA), that is more susceptible to mutations than nuclear DNA.

In a preliminary study we showed for the first time that more mutations in mtDNA are associated to a better outcome in CML patients. MtDNA mutations could affect the function of the mitochondrion, increasing its susceptibility to undergo apoptosis in response to TKI therapy. Therefore, stem cells from good responder patients could rely more on glycolysis for their survival. To the contrary, stem cells from poor responder patients, with intact mitochondria, could rely to a different metabolism, for e.g. being more dependent on mitochondrial respiration. The re-purpose of existing drugs targeting metabolic vulnerabilities represents a significant breakthrough in precision medicine and may lead to a rapid translation into clinical practice.

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Drug therapy can successfully prevent vomiting after chemotherapy but the majority of patients still suffer nausea. Patients differ in what symptoms they label as nausea which appears to be a cluster of several symptoms all of which may need separate treatment.

We will develop an App to find what symptoms each patient reports as nausea to see if we can improve it by treating each unique symptom. We will also monitor risk factors for nausea to see if we can prevent it occurring before treatment.

Dr Madelé van Dyk; Flinders University

Since the discovery kinase inhibitors (KIs), a class of targeted therapy against terminal cancers, progression free survival and overall survival has greatly improved. However, TKIs undergo complex metabolism via liver enzymes (CYP3A4), which is known for its substantial variability in activity. However, no marker to identify CYP3A4 activity in patients currently exists.

Due to the wide inter-individual variability, KI concentrations have varied up to >10 fold. Despite knowing this, variability between patients are inadequately addressed and a ‘one-size fits all’ prescribing is used. This clinical issue is widely recognised but still we do not account for this variability, resulting in some patients experiencing therapeutic failure or toxicity because the dose is not enough or too much.

Therapeutic drug monitoring (TDM) can address this, measuring drug concentrations and changing the dose until the patient’s concentration is in the ‘target concentration’. Based on my previous work I have shown that with the implementation of TDM, we can prolong progression free survival significantly and thus improve patient quality of life. I have also shown that patient characteristics can be used to account for this inter-individual variability. Therefore, this study will evaluate the capacity and benefit of TDM to optimise KI dosing and determine which patient characteristics can help to predict a better dose so that we can personalise treatment to each individual and maximising treatment and minimising side effects. Since the economic health benefit has never been evaluated, this study will the first to address this by performing a cost-benefit analysis.

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Professor Michael Sorich; Flinders University

The research will develop online tools that will help patients to work through difficult decisions about how and when to use an anti-cancer medicine for the treatment of cancer. It will do so by utilising innovative methods to comprehensively analyse a very large amount of data that has recently become available from both clinical studies of medicines and routine use of the medicines by patients. This analysis will allow high-quality predictions to be made regarding a patient’s specific likelihood of benefits and harms from using an anti-cancer medicine.

This research will help overcome barriers to the communication of key information and empower patients by providing doctors with a toolkit to present the treatment options and their key outcomes to the patient in a manner that is personalised to their specific circumstances and characteristics. By having this personalised information, patients can feel more confident and empowered to make the most appropriate decision for them specifically regarding their treatment and will be better prepared by having more accurate expectations for their treatment outcomes.

Additionally, the research will provide insight into the patient and disease characteristics influencing benefit and harms from treatment. These insights provide opportunities to better understand why medicines sometimes don’t work well for certain individuals and how this may be overcome.

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Dr Stephanie Reuter Lange; University of South Australia

Whilst there have been substantial improvements in the treatment of cancer, it remains that three out of 10 patients will not survive longer than five years, a result of either cancer progression or death from severe treatment-related side effects. Cancer medicines must be administered at a dose that is enough to treat the cancer, but not too much to cause toxic side effects. While this is well known, most cancer treatments are given as a “one-size-fits-all” amount. Given the large variability in response seen with many cancer medicines, this means that for the same dose some patients are likely to be under-treated and others a likely to be over-treated.

The concept of dose individualisation is tailoring the amount of drug administered to each individual patient to maximise tumour response and minimise side effects. This fellowship program will use computer-based modelling methods to identify dose individualisation strategies for best treatment practice. This will be conducted for a range of diverse projects that will illustrate the value in this approach to cancer treatment and provide a framework for determining the best use of new and existing cancer medicines.

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The emerging concept that tumour cells re-wire their energy production and can adapt this to survive under stress has raised the question of how best to therapeutically target metabolism of cancer cells.

We show that a specific AML subtype lacks this adaption capacity (metabolic plasticity) and is vulnerable to treatment with a new class of drugs that target metabolism. We will test these drugs in animal models of AML and investigate strategies to optimise the response to metabolic therapy.

Acute Lymphoblastic Leukaemia (ALL) treatment is toxic, expensive and ineffective for many patients, though the reasons for this are unclear. Even when successful, treatment can lead to debilitating late-effects, and an increased risk of early mortality. The gut microbiome is increasingly recognised for its role in cancer.

Here, we will investigate the role of the microbiome in ALL treatment response and late-effects, and develop approaches to improve outcomes across the life-course.

Most chronic myeloid leukaemia (CML) patients need continuous tyrosine kinase inhibitor (TKI) therapy to maintain remission.

We hypothesise that some leukaemic cells are kept in a “dormant” state, making them insensitive to TKI. This enables them to survive long-term and cause relapse if therapy ceases.

We will identify and characterise these dormant cells, then use novel drugs to activate and sensitise them to TKI-mediated eradication. This would provide a new curative treatment pathway in CML.

Alcohol is the leading cause of death and disability among 15-24 year olds globally.

Parents are the most common source of alcohol for underage drinkers, leading to risky drinking, poor mental health and alcohol dependence in adulthood. We know little about parents’ views on the ages of drinking onset that are acceptable.

This study will examine parenting styles and parents’ views about their adolescents drinking to develop new messaging to reduce parental supply.