2015 Funded Translational Research Projects

Project: Super-enhancer templated RNAs as predictive biomarkers of BET inhibitor sensitivity in prostate and colorectal cancer

Investigators: Dr Ron Firestein (Lead Applicant), Dr Arun Azad, A/Prof Helen Abud, A/Prof Paul McMurrick, Prof Gail Risbridger, Dr Simon Wilkins
Research Organisations: Monash University, Hudson Institute of Medicine Research, Cabrini Health
Funding: $2,000,000 over 36 months
Project Description: Prostate and colorectal cancer are the two most common malignancies in Australia. Despite advances in early screening, there is significant need to bring new treatments to patients. Herein, we provide strong rationale for use of a targeted class of epigenetic modulators, termed BET inhibitors, in a subset of prostate and colorectal cancers. Our preliminary results in preclinical models show that BET inhibitor sensitivity is predicted by the presence of distinct enhancer RNAs. We aim to translate our findings directly to patients by characterising the utility of enhancer RNAs to predict BET inhibitor response in a biomarker-informed clinical trial setting.

Project: Understanding the Biological Basis of Cancer Cachexia

Investigators: Professor Nick Hoogenraad (Lead Applicant), A/Prof Hamsa Puthalakath, Dr Amelia Johnston, Prof Andrew Scott, A/Prof John Silke, Prof Ulf Eriksson
Research Organisations: La Trobe University, Olivia Newton-John Cancer Research Institute, Karolinska Institutet (Sweden)
Funding: $2,466,000 over 36 months
Project Description: Cancer cachexia, a wasting condition that is one of the worst complications of malignancy, is responsible for up to 25% of cancer deaths and has no current effective treatment. We have developed antibodies which effectively block this condition in preclinical models. This proposal aims to assess this new treatment in patients and to develop blood and imaging biomarkers that can identify cachexia.

Project: Targeting mutant p53 in oesophageal cancer 

Investigators: Prof Wayne Phillips (Lead Applicant), A/Prof Lara Lipton, A/Prof Michael Michael, Dr Jayesh Desai, A/Prof Niall Tebbutt, Dr Nicholas Clemons, Dr Cuong Duong, Dr Ben Markman, Dr Andrew Haydon
Research Organisations: Peter MacCallum Cancer Centre, University of  Melbourne, The Royal Melbourne Hospital, Austin Health, Monash Health, Alfred Health
Funding: $1,853,674 over 36 months
Project Description: This project will test the effectiveness of a new drug (APR-246) for the treatment of oesophageal cancer. APR-246 targets a gene mutated in over 80% of oesophageal cancers and has potent anti-tumour activity in laboratory models. It will be tested as a single agent, and in combination with standard chemotherapy, in patients with advanced oesophageal cancer. We will also undertake laboratory studies to better select patients who will most benefit from APR-246, to establish a blood test to monitor patient response and disease recurrence, and to identify new drug combinations that increase the effectiveness of APR-246.

Project: Vaccination against Adenoid cystic and Colorectal Carcinoma Using MYB cDNA - VACCUMeD Clinical Trial - Immune Modulatory Therapy in Colorectal and Adenoid Cystic Carcinoma 

Investigators: Professor Robert Ramsay (Lead Applicant), Dr Jayesh Desai, A/Prof Benjamin Solomon, A/Prof Michael Michael, A/Prof Phillip Darcy, Mrs June Cory, Dr Jordanne Malaterre, Prof John Zalcberg, Dr Emma Link
Research Organisations: Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Monash University
Funding: $1,343,655 over 36 months
Project Description: The tumour cells in patients with bowel cancer and certain head and neck cancer harbour a particular factor that orchestrates multiple pro-cancer processes. We have found that the aberrant production of this factor allows the specific targeting of these cancers by a novel vaccine. Using this vaccine in combination with the blockade of the recently discovered immune system check-point regulators we have developed robust pre-clinical evidence for symptom-free cancer control and cures. In this new project we aim to advance the vaccine into patients to test its safety and as a secondary aim to monitor for evidence of vaccine efficacy. If successful, this specific vaccine has broad applicability and more widely the concept is readily transferable to other cancers.

Project: Augmented immune targeting of a myeloma-specific tumour antigen

Investigators: Associate Professor Jake Shortt (Lead Applicant), Prof Andrew Spencer, A/Prof John Reynolds, Prof Ricky Johnstone, Dr Hang Quach, Dr George Grigoriadis, Dr Anna Kalff, Dr Tiffany Khong, Dr Patricia Walker, A/Prof David Powell
Research Organisations: Alfred Health, Monash Health, Monash University, Australian Centre for Blood Diseases, Peter MacCallum Cancer Centre, The University of Melbourne, St Vincent's Hospital Melbourne, Peninsula Health
Funding: $1,974,342 over 36 months
Project Description: Myeloma is an incurable cancer of the bone marrow plasma cell. Recent advances have been made using treatments that stimulate the immune system to remove these cancerous plasma cells. We have developed a treatment called MDX1097 that recognizes and binds only to cancerous plasma cells. Cells coated with MDX1097 then become visible to the immune system. Thalidomide is very useful in myeloma as it kills cancerous plasma cells while also stimulating the immune system. We will combine a thalidomide derivative with MDX1097 in a clinical trial for Victorian myeloma patients.

 

2015 Funded Health Services Research Projects (Funded in partnership with the Victorian Integrated Cancer Services)

Project: The CRISP Trial: an RCT of a risk assessment tool to implement risk-stratified colorectal cancer screening in primary care 

Investigators: Prof Jon Emery (Lead Applicant), Prof Mark Jenkins, Prof Finlay Macrae, A/Prof Marie Pirotta, Dr Driss Ait Ouakrim, Dr Jennifer Walker, Dr Fiona Walter, Prof Ingrid Winship, Dr Patty Chondros, Dr Adrian Bickerstaffe, Mr Richard De Abreu Lourenco, Prof Lyndal Trevena
Research Organisations: The University of Melbourne, Royal Melbourne Hospital, University of Cambridge, University of Technology Sydney, University of Sydney
Funding: $300,000 over 36 months
Project Description: There is a mismatch between people’s use of bowel cancer screening tests through faecal occult blood testing or colonoscopy and their individual risk of bowel cancer. Building on the work of our NHMRC Centre for Research Excellence (CRE) on Optimising Colorectal Cancer Screening, this trial will test the effect of an electronic risk assessment tool, implemented in general practice, on use of the most appropriate screening test for bowel cancer based on a person’s risk of developing the condition in the next five years.

Project: Better quality of life for cancer patients through early e-health program 

Investigators: Prof Terry Haines (Lead Applicant), Prof Helen Truby, Dr Catherine Huggins, A/Prof Judith Bauer, Ms Maryanne Silvers, Ms June Savva, A/Prof Helena Frawley, Prof Julie Barnett, Mr Paul Cashin, Mr Liang Low
Research Organisations: Monash University, Monash Health, Cabrini Health, University of Queensland, University of Bath (UK)
Funding: $299,981 over 36 months
Project Description: Patients with stomach or oesophageal cancer have very poor prognosis. Tailored nutrition care provided to patients prior to commencing cancer treatment improves health outcomes. Currently, health services have limited capacity to deliver effective preadmission nutrition care, resulting in patients commencing cancer treatment in a very poor nutritional state. This study examines if using an innovative standardised e-platform enables a dietitian to effectively deliver a tailored very early nutrition intervention to improve body weight, body muscle and fat stores and Quality of Life of those newly diagnosed with stomach or oesophageal cancer.

Project: Shared care of Colorectal cancer survivors – A randomised controlled trial of hospital-based follow up versus shared hospital / community follow up for survivors of colorectal cancer 

Investigators: A/Prof Michael Jefford (Lead Applicant), Prof Penelope Schofield, Prof Jon Emery, Prof Eva Grunfeld, Prof Alexander Heriot, Dr Andrew Martin, Mr Richard De Abreu Lourenco, Mrs Dorothy King
Research Organisations: Peter MacCallum Cancer Centre, Swinburne University, The University of Melbourne, University of Toronto (Canada), University of Sydney, University of Technology Sydney
Funding: $300,000 over 36 months
Project Description: After finishing treatment for bowel cancer, survivors can experience a range of issues – with ongoing side effects, emotional, psychological and practical concerns. Most people have follow-up with their cancer specialists (surgeon or oncologist). However, people often report needs that are not met. Follow up with general practitioners (GPs) is a reasonable option for some survivors. A combination of follow up with cancer specialists and GPs (called shared care) may offer a range of advantages and may be cheaper than the standard follow up model. This study will compare standard follow up to a shared care model for bowel cancer survivors

Project: Development of an Ethical Framework and Resources for Decision-making in the Application of Genomic Sequencing and Personalised Medicine in Paediatric Oncology

Investigators: Dr Maria McCarthy (Lead Applicant), Prof Lynn Gillam, Dr Francoise Mechinaud, Mr Richard De Abreu Lourenco, Prof Sylvia Metcalfe, A/Prof Paul Ekert, Dr Rachel Conyers, Dr Peter Downie, Dr Michael Sullivan
Research Organisations: Murdoch Childrens Research Institute, Royal Children's Hospital, The University of Melbourne, University of Technology Sydney, Monash Children's Hospital
Funding: $250,839 over 36 months
Project Description: Many rare and relapsed childhood cancers are difficult to cure. A new treatment approach called ‘personalised’ medicine involves whole genome sequencing with the aim of identifying specific drugs to target the tumour. This is an exciting new field but there are many complex issues. In particular there are ethical questions about which patients should be offered genomic sequencing, who should pay for this and for potentially expensive experimental drugs, and how risks should be managed. This study will identify preferences of families and healthcare professionals develop an ethical framework to help decision-making and develop much-needed informational and educational resource.

Project: A Randomised Phase 2 study to examine feasibility of Standardized, Early Palliative Care for patients with Advanced Cancer

Investigators: A/Prof Jennifer Philip (Lead Applicant), Prof Peter Hudson, Prof Jon Emery, A/Prof Linda Mileshkin, Ms Anna Collins, A/Prof Brian Le, A/Prof Vijaya Sundararajan, Ms Susan Hanson, A/Prof Caroline Brand, Dr Sibilah Breen, Dr Sam Mancuso, Dr Sonia Fullerton, Ms Soula Ganiatsas
Research Organisations: St Vincent's Hospital Melbourne, Centre for Palliative Care, The University of Melbourne, Peter MacCallum Cancer Centre, Melbourne Health, Cancer Australia, Palliative Care Research Network of Victoria
Funding: $296,513 over 36 months
Project Description: Patients with advanced cancer have unmet symptom burden and information needs. Early evidence reveals referral to palliative care appears to address these needs. Yet gaps in understanding remain, particularly around the timing of palliative care for specific cancers, and its impact upon the patient, family and health care system. This study will explore introducing standardized early palliative care at designated time points for patients with advanced lung, breast, prostate and brain cancers. We anticipate early palliative care will improve support and experiences of care for patients, and reduce the current variations in quality cancer care. 

Project: Telehealth for Rural Palliative Cancer Care: A prospective controlled pilot study of video-consultations for patients & carers of a domiciliary palliative care service 

Investigators: A/Prof Peter Poon (Lead Applicant), Dr Leeroy William, Dr Michael Franco, Dr Jackyn Yoong, Dr Beisi Zhang
Research Organisations: Monash Health, Monash University, West Gippsland Health
Funding: $141,000 over 36 months
Project Description: Regional Australia desperately needs palliative care (PC) expertise for cancer patients. Telehealth uses telecommunications technology to deliver health services over distances. There is surprisingly little research in telehealth to support bedside community PC. Video-consultation by metropolitan PC physicians to home/bed-bound patients during nursing visits has great potential to model an invaluable process to support PC needs throughout our ageing rural population. Our study addresses a viable paradigm to deliver earlier specialist palliative care to rural cancer patients especially those with difficult-to-manage symptoms. Working together with rural medical practitioners, this will lead to improved care planning, carer support and multidisciplinary management.

 

2015 Workforce Funding Recipients

Dr Sashendra Senthi
Victorian Cancer Agency Clinical Research Fellowship
Monash University
Improving programmed death 1 inhibitor response against metastatic melanoma with radiotherapy: optimising combination treatment and utilising genetic biomarkers
Metastatic melanoma generally confers poor survival. While immune activating drugs can extend survival beyond 10 years for some, they cause significant toxicity without benefit in others. Combining these drugs with radiotherapy can improve the proportion that benefit. I seek to optimise the synergism between immune activating drugs and radiotherapy and reveal the genetics underlying response. This will improve metastatic melanoma survivorship, limiting treatment to those with a chance of response and cost-effectiveness, allowing more rapid approval of immune activating drugs for other indications.

Dr Mark Shackleton
Victorian Cancer Agency Clinical Research Fellowship
Peter MacCallum Cancer Centre
Translating melanoma dicoveries from the laboratory to the clinic
Cancers usually arise from one cell. However, as tumors grow, the cells that comprise them often become different from one another. The ability of cancers to produce diverse cell types is called cancer heterogeneity and is a major driver of cancer recurrence and of resistance to cancer treatment. My research will focus on understanding the nature of heterogeneity in melanoma, and how the body’s immune system reacts against tumors as they change and spread. I will also test new combination treatments as well as undertake clinical studies to account for the challenges presented by cancer heterogeneity in patient management.

Dr Gabriela Brumatti
Victorian Cancer Agency Mid-Career Research Fellowship
The Walter and Eliza Hall Institute of Medical Research
Identifying new therapeutic strategies using the new clinical drug birinapant, to overcome drug resistance and treat blood cancers such as Leukaemias
Acute Myeloid Leukaemia (AML) is an aggressive cancer of blood cells, affecting people of all ages. Less than 50% of AML patients can be cured with the current treatments. Thus, new therapeutic strategies are needed. We have been at the forefront of understanding how a new anti-cancer drug, birinapant, kills cancer cells. This project will test whether birinapant, in combination with other clinical drugs, can be used to treat leukaemia. The aim of our research is to determine how these drug combinations can be effectively used to increase the chances of cure, with reduced side effects, and benefit patients.

Dr Andrew Deans
Victorian Cancer Agency Mid-Career Research Fellowship
St Vincent's Institute of Medical Research
Improved Use of Gene Panel Testing in Familial Breast Cancer Clinics
Since 1997, genetic testing of BRCA1/BRCA2 has been offered to selected women attending Familial Cancer Centres in Victoria. For the majority of women (~85%) these tests are uninformative (negative). Continued research has identified additional genetic risk factors for breast cancer that have not been translated into clinical practice due to lack of evidence and defined process. This proposal will build the evidence base required for an expanded set of tests – “gene panel testing” – to be delivered. In particular, expertise in functional assays will be used to identify cancer-predisposing variants for risk estimation and clinical evaluation.

Dr Kylie Gorringe
Victorian Cancer Agency Mid-Career Research Fellowship
Peter MacCallum Cancer Centre
Personalised risk evaluation of ductal carcinoma in situ 
When a woman is diagnosed with ductal carcinoma in situ (DCIS), she is told by her doctor that there is a chance it will return as cancer. But what chance? The risk provided is an average and may not be accurate for her specifically. Wouldn't it be better to have precise, personal risk to base treatment choice on? Strong candidate biomarkers will be tested using clinical-grade assays on 200-400 DCIS tissues with patient outcome data. The best markers will be developed into a model to give a robust risk value on which to base treatment decisions.

Dr Lev Kats
Victorian Cancer Agency Mid-Career Research Fellowship
Peter MacCallum Cancer Centre
Development of personalised therapy for leukaemia based on a specific genetic mutation
Novel therapies for acute myeloid leukaemia (AML) represent an area of urgent unmet clinical need. Mutations in enzymes known as IDH1 and -2 are amongst the most common in AML and offer a promising opportunity for development of a new generation of targeted drugs that specifically kill leukemic cells without affecting normal tissues. Herein we propose to use advanced genetic and pharmacological tools to comprehensively analyse the role of IDH dysfunction in leukaemia initiation, development and progression. We expect that our findings will guide ongoing and future clinical trials for novel therapies of AML.

Dr Enid Lam
Victorian Cancer Agency Mid-Career Research Fellowship
Peter MacCallum Cancer Centre
Evaluation of tumour heterogeneity in the initiation and maintenance of AML and following response to therapy
The advent of global sequencing technologies has highlighted that every cancer displays marked heterogeneity in DNA mutations and gene expression programs. This intra-tumour heterogeneity underpins the unpredictable natural history of all malignancies including acute myeloid leukaemia. It is also the primary driver for the variable response often observed to conventional and targeted chemotherapies. Deciphering this complexity at the single cell level holds the key to a more comprehensive understanding of the biology of cancer. Furthermore, understanding the adaptive responses to therapies holds the promise of improving therapeutic outcomes.

Dr Rodney Luwor
Victorian Cancer Agency Mid-Career Research Fellowship
The University of Melbourne
Overcoming Tumour Resistance to Epidermal Growth Factor Receptor Targeted Therapy
Treatment of cancer patients using growth factor receptor inhibitors is only moderately successful due to resistance mechanisms developed by the tumour, which allow key pro-cancerous signals to continue, unaffected by treatment. We recently discovered a novel role of the key signalling molecule in cancer, STAT3 in mediating resistance to cancer treatment targeting the epidermal growth factor receptor. Therefore, this research project will evaluate the blockade of STAT3 as a method to re-sensitize tumours to anti-EGFR based therapy. This work will provide evidence for the use of such novel combinational therapy in cancer patients clinically.

Dr Ian Majewski
Victorian Cancer Agency Mid-Career Research Fellowship
The Walter and Eliza Hall Institute of Medical Research
New approaches to improve the diagnosis and clinical management of childhood cancer
Cancer results from mutations that disrupt the mechanisms that regulate cell growth and survival. Advances in sequencing technology mean that it is possible to profile a cancer to identify the mutations that supporting its growth. This application is focused on using this knowledge to match patients with effective therapies. While initially focused on childhood leukaemia, we aim to build new diagnostic systems that will improve outcomes for all cancer sufferers.

Dr Carl Walkley
Victorian Cancer Agency Mid-Career Research Fellowship
St Vincent's Institute of Medical Research
Development and application of preclinical models to improve cancer outcomes
I am interested in developing models of human cancer to improve our understanding of these cancers (bone cancer and blood cancer) and to use these models to identify and test new therapies.

Dr Renea Taylor
EJ Whitten Mid-Career Research Fellowship
Monash University
Targeting Castrate-Tolerant Prostate Cancer Cells
This proposal addresses one of the more important challenges in cancer: what cell population ‘drives’ cancer progression and how can it be effectively targeted? The goal is to define the prostate cancer cells that survive treatment and determine better ways to kill them. Eliminating these cells earlier in disease progression will lead to increased survival for men with prostate cancer.

Dr Dane Cheasley
Victorian Cancer Agency Early Career Seed Grant
Peter MacCallum Cancer Centre
Improving early detection and management of women at risk of developing interval breast cancer
Breast cancers diagnosed after a negative mammogram but prior to the next scheduled screening are termed “interval cancers”, and comprise 25-30% of breast cancers diagnosed in women undergoing population-based mammography screening. Interval cancers have a worse prognosis compared to screen detected cancer and is a key limitation on the effectiveness of population based mammographic screening. We will identify inherited features of interval cancers that can be used to prospectively identify women at risk of developing an interval cancer, so that modification of screening can reduce the interval cancer rate and reveal new treatment options.

Dr Elizabeth Christie
Victorian Cancer Agency Early Career Seed Grant
Peter MacCallum Cancer Centre
Clinical translation of a newly discovered transcriptional fusion involving the multidrug resistance transporter (ABCB1) in recurrent drug resistant ovarian cancer
We recently conducted the first whole genome sequence analysis of recurrent and end-stage high-grade serous ovarian cancer (HGSC) (Patch et al Nature 2015) and discovered fusion of the multidrug resistance transporter gene, ABCB1, to an upstream gene, resulting in profound overexpression of this drug efflux pump. Using unique patient derived cell lines with the fusion we will explore approaches to reverse drug resistance in recurrent ovarian cancer.

Dr William Figgett
Victorian Cancer Agency Early Career Seed Grant
The University of Melbourne
Development of monoclonal antibodies and chimeric antigen receptor T cells targeting the BAFF receptor TACI for treating chronic lymphocytic leukaemia in pre-clinical models
Chronic lymphocytic leukemia (CLL) is a cancer of the immune system cells, where cancer cells proliferate in the blood. The immune system is compromised, and recurrent infections are a major problem. We will generate antibodies that bind specifically to TACI, which is a receptor on the surface of some cancer cells and some types of immune system cells. We predict this will change the signals that are given by the cancer cells to repress the immune system, which would be reprogrammed to activate and help fight against infections and cancer. Alternatively we will modify immune cells to eliminate TACI-expressing cells.

Dr Jacqui Frowen
Victorian Cancer Agency Early Career Seed Grant
Peter MacCallum Cancer Centre
A prospective study of swallowing and voice outcomes after treatment for small-cell lung cancer
Lung cancer remains the most common cancer in the world, with high incidence and mortality rates. Patients with lung cancer are at risk of swallowing problems (dysphagia) and voice problems (dysphonia) due to the cancer itself or its subsequent treatment. Dysphagia in particular can be devastating, and if severe may cause fatal complications. This study will investigate swallowing and voice problems prior to and again after treatment in patients with small-cell lung cancer, to gain a detailed insight into the extent and nature of this problem so that patients can be more appropriately managed and significant treatment complications avoided.

Dr Lahiru Gangoda
Victorian Cancer Agency Early Career Seed Grant
La Trobe University
Understanding the molecular mechanisms regulating chemotherapeutic drug resistance
Bowel cancer is the most common form of cancer in Australia with 15,000 people diagnosed each year.  Chemotherapy is the first line of treatment to kill cancer cells in patients with advanced bowel cancer. Cancer patients may develop resistance to anti-cancer drugs resulting in the failure of the treatment. This project seeks to identify mechanisms by how cancer cells resist treatment. Furthermore, we will silence key proteins (identified in our preliminary analysis) that are thought to play important roles in developing drug resistance. Silencing these key proteins may result in efficient killing of cancer cells.

Dr Dale Garsed
Victorian Cancer Agency Early Career Seed Grant
Peter MacCallum Cancer Centre
A unique cohort of long-term survivors of high-grade serous ovarian cancer: Molecular insights into exceptional responses to chemotherapy
High-grade serous ovarian cancer (HGSC) is one of the deadliest cancers affecting women due the tendency of these tumours to develop chemotherapy resistance. This project aims to molecularly investigate why a small subset of patients with HGSC have an outstanding response to chemotherapy. Tumours collected from exceptional responders will be genetically profiled to identify changes in DNA associated with enhanced sensitivity to chemotherapy and long-term survival. We believe that understanding how these unusual women beat the odds may provide insights into improving outcomes of patients with HGSC that have a more typical disease trajectory.

Dr Lesley Stafford
Victorian Cancer Agency Early Career Seed Grant
Royal Women's Hospital
Development and evaluation of a brief psychoeducational intervention to support parents with cancer who have young children
Cancer in a parent with young children is stressful for the entire family. Parents have high rates of anxiety and depression and their children are at increased risk of poor psychosocial outcomes. Parents worry about meeting their children’s emotional and information needs and about the impact of the illness on their children. This project will develop and evaluate a novel, accessible and sustainable intervention to improve parenting skills, confidence and quality; enhance children’s psychosocial adjustment, reduce parental stress and psychological morbidity and improve family communication among parents receiving curative treatment.