Current Dalgleish Centre Projects

Rather than seeking to kill cancer cells, “differentiation therapies” aim to reprogram corrupted cells to resume their normal developmental trajectory, leading to maturation, loss of self-renewal and exhaustion. This fundamentally different strategy has already had significant clinical success in acute myeloid leukaemia but is yet to be tested in other cancer types. Herein we propose to directly target the self-renewal circuitry of myeloma cells using an epigenetic drug regimen. This combination constitutes a new class of anti-myeloma therapy that is distinct from current treatments that are largely focussed on the protein recycling system and antibodies that engage cell surface receptors. The main goals of this project are to identify genes responsible for the anti-tumour responses of myeloma cells to our epigenetic drug combination. The expected outcome of this strategy is to validate new therapeutic targets and potential biomarkers that might improve the quality of the current treatments and the survival expectancy of myeloma patients.

Associate Professor Lev Kats
Peter MacCallum Cancer Centre

Professor Stephen Nutt
Walter and Eliza Hall Institute of Medical Research

Dr Simon Willis
Walter and Eliza Hall Institute of Medical Research

Previous research conducted by the Johnstone laboratory has demonstrated that multiple myeloma cells show a particular sensitivity to drugs that inhibit the enzymes P300 and CBP. We wish to identify the genes and so called “non-coding” RNAs that are important for the anti- multiple myeloma response to P300/CBP inhibition. This will help us decipher how and why multiple myeloma cells are so dependent on these enzymes and will shed light on the mechanisms of action of these novel therapeutic agents.

Professor Ricky Johnstone
Peter MacCallum Cancer Centre

Drug resistance is a major challenge for treating multiple myeloma. Cancer cells can escape the harmful effects of chemotherapy or targeted therapy and survive by modifying translation, a process of manufacturing new proteins from a genetic material made from DNA called messenger RNA (mRNA). Our project aims to understand how multiple myeloma cells modify mRNA translation capacity and efficacy to acquire resistance to multiple myeloma. The research will discover novel mechanisms of drug resistance and disease progression driven by altered mRNA translational activity, identify new vulnerabilities in multiple myeloma cells and provide the rationale for developing new therapies to prevent disease recurrence and improve outcome.

Dr Jian Kang
St Vincent’s Institute of Medical Research

Our research aims to identify molecular signatures of disease progression to enable the development of biomarkers (tests) that can predict a patient’s response to treatment and the best treatment pathways to choose when relapse occurs. Accurate biomarkers have the potential to enable personalised treatments, advanced disease monitoring and improve survival. This project will characterise the molecular changes associated with responses to two emerging therapies in multiple myeloma and define the molecular changes in bone marrow trephine samples accrued on clinical trials. We aim to identify predictors of response or resistance to therapy by comparing immune and molecular signatures in samples from patients with refractory and relapsed multiple myeloma with those who achieved response. The analysis will enable us to develop methods to identify patients who will benefit from therapy and could reveal new pathways that promote drug resistance.

Associate Professor Elaine Sanij
St Vincent’s Institute of Medical Research

Standard treatments for multiple myeloma include autologous stem cell transplants (cells obtained from the patient themselves), chemotherapies, and medications such as Bortezomib and Lenalidomide. New treatments have been developed recently, including immunotherapies such as chimeric antigen receptor T-Cells (CAR-T). To date, two CAR T-Cell therapies have been approved by the FD that target a molecule called BCMA on myeloma cancer cells. Although the clinical outcome seemed promising, some patients did have relapsed disease because the cancer cells lost the targetable BCMA molecule. To address this issue, we discovered a novel target molecule that is widely expressed on myeloma cancer cells after the standard treatment with Bortezomib. By targeting this new molecule, CAR T-Cells can be used in combination with Bortezomib to eliminate the tumour. In this project, we will provide the pre-clinical effectiveness and safety data using multiple myeloma animal models. Based on the evidence, we expect the project will ultimately lead to future clinical trials and better outcomes for multiple myeloma patients.

Dr Joe Zhu
Peter MacCallum Cancer Centre

Multiple myeloma is one of the most expensive cancers to treat and is characterised by repeated hospital admissions. Novel therapies have delivered significant improvements in overall and progression-free survival, but this has brought new challenges.  With improved disease control patients can remain on treatment for many years, which has resulted in extended periods of specialist hospital surveillance, increased burden of travel, inconvenience, and cost for patients and carers - especially for those from regional, rural and remote areas. The requirement for extended health service use also adds burden to an already resource constrained health system. Whilst there is urgent need for contemporary models of care that address patient and system level benefits, multiple myeloma teams across Australia have had difficulty in sustaining patient self-administration programs because of inflexible systems, drug sterility timeframes, risk management considerations, beliefs about patient capability and resourcing. Our team has successfully implemented and sustained nurse-enabled, patient self-administration programs (Peter MacCallum Cancer Centre and St Vincent’s hospital) which indicated considerable patient and system level benefits. Understanding the barriers faced by other centres to implement and sustain these programs and sharing enablers to success from the Peter Mac and St Vincent’s teams, presents an important opportunity to develop robust, evidence-informed national implementation strategies that support the national scalability of programs to deliver existing and emerging novel therapies.

Hayley Beer
Peter MacCallum Cancer Centre

Multiple myeloma has been associated with a significantly improved survival over the last three decades, however morbidity remains high and is compounded by treatment-related chronic toxicities. This results in the highest symptom burden of all haematological malignancies and the poorest quality of life; patients commonly experience fatigue, bone pain, sleep problems, financial hardship and functional decline, all of which impact on physical, emotional and social health.  Furthermore, given the median age at diagnosis (65-70 years) patients have a high risk of concurrent and/or new diagnoses of additional age-related diseases causing disability and adding to the complexity of their care.  To our knowledge no formal survivorship/ long term care model has been developed to meet the unique needs of the multiple myeloma patient. Using implementation science frameworks we will conduct a feasibility implementation study, co-designing strategies to implement a novel survivorship nurse and pharmacist-led multidisciplinary clinic that is acceptable for multiple myeloma patients, carers and their treating teams, whilst also conducting a micro-costing study (using administrative and survey data) to evaluate the program cost per patient from a health system perspective.

Associate Professor Amit Khot
Peter MacCallum Cancer Centre

Multiple myeloma patients are typically treated with autologous stem cell transplantation, immunomodulatory drugs, proteasome-inhibitors and monoclonal antibody therapies. Chimeric antigen receptor (CAR) T-cell therapy as a fourth line treatment is relatively successful in treating refractory/ relapsed multiple myeloma patients, with an overall response rate of 80%. Despite this, many patients eventually relapse, and resistance mechanisms include CAR T-Cell trafficking, exhaustion, antigen escape and an immunosuppressive tumour microenvironment. To ensure that CAR T-Cells can have long-term responses in multiple myeloma, we need new strategies to overcome resistance. In this project, we propose two approaches: the first is to understand the tumour microenvironment of patients that receive immunomodulatory drugs and study the changes that occur at the tumour site; the second is evaluating the use of engineered switch CAR T-Cells that can specifically function in an immunosuppressed tumour microenvironment in combination with immunomodulatory drugs. These approaches will overcome issues such as CAR T-Cell trafficking into the tumour and immunosuppression and may lead to the discovery of additional pathways or proteins that can be targeted with switch CAR T-Cells.

Dr Criselle D’Souza
Peter MacCallum Cancer Centre

Multiple myeloma is characterised by neoplastic expansion of plasma cells in the bone marrow. Evidence suggests that malignant plasma cells form a unique bone marrow microenvironment that regulates their long-term survival and resistance to conventional chemotherapy. However, the precise role of microenvironments and the factors that regulate these interactions are poorly understood. Recently, using a mouse model of multiple myeloma that allows clonal tracing of myeloma microenvironments, we performed single cell RNA sequencing to identify genes that are dysregulated in neoplastic cells compared to their healthy plasma cell counterparts. We identified 72 dysregulated genes including novel candidates with tentative links to bone marrow microenvironment interactions that have no previous association with multiple myeloma biology. In this project, we will use a novel multiple myeloma gene editing protocol that we have established in the Hawkins laboratory to characterise the biological function of candidate genes in vivo. Our goal is to identify genes that are central regulators of bone marrow microenvironments with the view of developing therapeutic interventions that can target these interactions in the future.

Associate Professor Edwin Hawkins
Walter and Eliza Hall Institute of Medical Research

A key unmet need in multiple myeloma is the treatment of high-risk disease, where survival remains suboptimal. One of the most important factors for high-risk disease is the development of extramedullary multiple myeloma (EMM). In EMM, myeloma cancer cells leave the bone marrow and deposit and grow in bone or soft tissue or develop into plasma cell leukemia. Current data suggest inferior outcomes for these patients even after receiving new treatment modalities such as bispecific antibodies (artificial proteins that can bind to two different targets simultaneously) and CAR-T cells (a patient’s own T cells that have been reengineered to better target cancer cells). Patients with EMM generally have a survival of 38 months compared to 109 months for patients without EMM. Unfortunately, EMM is largely understudied, making the development of personalised treatments for these patients challenging. This study will be the largest and most comprehensive profiling study of EMM to date. We will profile the myeloma cells from bone marrow and extramedullary tissue from patient tissues and will investigate genetic changes, changes in the level of activity of genes, and the normal cells of the organ where the EM lesions are growing. This will allow us to identify unique features of the extramedullary tissue that could be used to stratify the disease and can be tested as targets for new treatments.

Dr Anna Trigos
Peter MacCallum Cancer Centre

Despite a widening array of novel therapies, multiple myeloma remains incurable in the majority of cases, hence there is an urgent unmet need to develop novel treatment strategies - especially those that engage different mechanisms of action compared with agents currently used in the clinic. Analysis of samples from multiple myeloma patients using sophisticated ‘omics’ methodologies have highlighted the tremendous genetic and non-genetic diversity of multiple myeloma, however, the rate that this knowledge is being translated into improved patient outcomes is currently too slow. Historically, a major impediment slowing the discovery of new therapies for myeloma has been the scarcity of immune competent mouse models that recapitulate the diversity of genetic lesions that exist in human myeloma. Such models represent an essential platform to: (1) identify molecular factors that predict resistance; and (2) rapidly evaluate the efficacy of rationally designed combination regimens that are based on mechanistic understanding. In this project we will build and implement a state-of-the-art ‘mouse myeloma hospital’ that will allow us to trial clinical protocols that closely mimic those in humans and then profile the effects of therapies on multiple myeloma cells.

Associate Professor Lev Kats
Peter MacCallum Cancer Centre

We use specialised scans (positron-emission tomography/computerised tomography or PET/CT scans) to identify EMD tumours. PET/CT scans use radioactive sugar to identify the tumours due to their high metabolic requirements; this means PET/CT scans may also contain important information about tumour metabolism and behaviour more broadly. Biopsies of tumours are required to confirm the diagnosis, however, sometimes biopsies can be challenging if the tumour is located in a difficult spot to biopsy. In previous work, we have shown that ‘liquid biopsies’ taken from blood tests can identify the mutations within EMD tumours. Our current project will combine PET/CT and liquid biopsies to answer important questions about the biology of EMD. We will use artificial intelligence to interpret PET/CT scans in EMD patients to highlight new associations between scan results and patient outcomes. Furthermore, we will greatly expand the liquid biopsy work to describe the ‘circulating genome’ of EMD patients and link this genetic information with the behaviour of tumours as shown on PET/CT scans in addition to clinical outcomes. This will provide information on how EMD arises and behaves to allow us to identify new therapies that can be targeted to the specific biology of these tumours, and which will improve outcomes for patients with this very difficult- to-treat form of multiple myeloma.

Dr Nicholas Bingham
Monash University and Alfred Health

In dissecting the mechanism of action of steroids in inflammation and myeloma, we have identified a key protein that is activated in response to exposure to steroids that avoids many unwanted steroid side effects. In this research we will exploit this discovery to kill malignant plasma cells directly, while bypassing undesirable steroid toxicities. We will use the mechanistic insight from our studies to learn more about how myeloma cells develop resistance to steroids, and how to overcome this resistance. Our research plan incorporates two complementary approaches. The first is a drug discovery pipeline that will identify small molecules capable of killing myeloma cells with a steroid-like mechanism that bypasses unwanted side effects. The second approach will use messenger RNA (mRNA) technology to deliver a steroid-like payload to myeloma cells without activating their steroid receptors. Success in these aims will provide a new approach to myeloma therapy that may complement or even replace the need for steroids and their attendant side effects.

Professor Jake Shortt
Monash University and Monash Health