|University of Melbourne
Exploring a novel target for therapeutic intervention in acute myeloid leukaemia.
AML is a common form of leukaemia and is increasing in frequency due to an ageing population. Cohesin is a protein that functions in cell division and gene regulation16. 13% of AMLs have cohesin mutations2,3. Synthetic lethal approaches hold great potential for cancer treatment by seeking to exploit the ‘Achilles Heel' of cancers, where mutation in a cancer gene sensitises cells to particular drugs. Our research will develop synthetic lethal drugs that target leukaemias with cohesin mutations. The research may lead to personalised medicine for a subset of patients with AML.
Role of SOX2 a stem cell protein in metastatic melanoma.
New Zealand has the highest rate of melanoma in the world and the treatment of metastatic melanoma remains a major challenge. An improved understanding of the molecular mechanisms underlying melanoma pathogenesis would allow the development of more effective therapies. The mechanisms of melanoma invasion are poorly understood. The SOX2 protein has recently been discovered to be expressed in human metastatic melanoma. We seek to investigate how the SOX2 gene is regulated, and to investigate its effects on melanoma behaviour, both in a series of low passage cell lines in culture, and when grown as xenografts in mice.
Defining therapeutic targets in small cell ovarian cancer.
Inhibitors of the DNA repair enzyme PARP-1 are a new class of anticancer agent. They are being clinically trialled for Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a treatment-refractory form of ovarian cancer striking very young women. Most patients succumb to their disease within 1-2 years of diagnosis. Research to date provides no evidence to propose any effective treatment modality for these patients. We have discovered consistent deregulation of three candidate biologic mechanisms in SCCOHT tumours that are clinically actionable. Our objectives are to dissect and understand the contribution of each mechanism on the malignant behavior of SCCOHT tumours using preclinical laboratory models, and accelerate translation of these discoveries toward clinical application..
Targeting ubiquitin pathways to control chronic inflammation
Development of cancer depends on molecular changes that cause cells to overcome normal protective mechanisms. Persistent inflammation is now recognised as one of the key features that enables tumour formation. This study will provide insight into the molecular mechanisms by which inflammatory signals from the tumour microenvironment are translated into pro-tumour signals. In particular, we aim to understand how proteins can be modified by addition of another protein to alter signaling. These studies will aid the development of compounds that can modulate the pro-tumour aspects of protein modifications for the treatment of cancer
Changes in immune cells in human melanoma metastases responding to therapy.
Immune therapy of cancer is one of the most exciting areas of cancer research and promises to revolutionise cancer treatment over coming years. However we still don't know exactly how best to manipulate the immune system in cancer – partly because we haven't been able to study successful immune attack on tumours. Through a collaboration with the Melanoma Institute of Australia, we have a unique opportunity to study immune cell activity in melanoma tumours that are responding to therapy. Our studies will help improve design of immune therapy for cancer, and enable this therapy to be tailored to individual patients.
The New Zealand Colorectal cancer patient journey: exploration of inequities by ethnicity, rurality and socioeconomic status.
Each year bowel cancer kills more New Zealanders than breast and prostate cancer combined. We know that patients living in rural areas, Maori and Pacific patients, and patients with a low socioeconomic status are more likely to die following a bowel cancer diagnosis. We don't know why. This research aims to find out if there are differences in the treatment these groups of people receive for their bowel cancer. With this information changes can be made to ensure that all New Zealanders get equally good treatment for bowel cancer, and that fewer patients die from this disease.
A case-control study to detect predisposition to 5-FU toxicity using a thymine loading test and urine collection
5-fluorouracil (5-FU) is widely used in the treatment of many cancers including colorectal and breast cancer. Unfortunately this useful drug is associated with life-threatening side effects in some patients. Despite extensive research it is still difficult to determine who is at risk of this toxicity. We aim to use a simple urine test to help predict those patients who can and cannot tolerate treatment with 5-FU. Our ultimate goal is to improve the safe use of this chemotherapy in patients with cancer.
Improved survival with cimetidine in early colorectal cancer: impact on the Immunoscore.
Bowel cancer is very common in NZ but cimetidine, a drug originally used to reduce stomach acid, appears to reduce the risk of bowel cancer recurrence and death. We want to look at how cimetidine improves the immune response to cancer and whether this could be a major part of how it improves outcomes. We will do this using a new test, the Immunoscore, which measures specific types of immune cells and their location within the cancer and strongly predicts patient outcomes. The study will see if patients who took cimetidine around their cancer operation have better Immunoscores than those who did.
Evaluating the effectiveness of subcutaneous needle drainage of lower limb lymphoedema in palliative care patients: a multi-centre study.
Lymphoedema is a common symptom affecting patients with malignancies and is caused by fluid build-up in the limb(s), leading to symptoms of heaviness, pain, reduced mobility and disfigurement. Current treatment mainly includes massage and bandaging, which is limited. Draining the fluid build-up with needles is a procedure performed around the world but with little evidence of its value and potential complication rates. A pilot of 10 patients at Nurse Maude Hospice showed promising results. This study proposes assessing quality of life before and after the procedure and complications data in four New Zealand sites to achieve reasonable numbers of patients.
Does BCL6 Blockade Allow the Induction of Apoptosis in GBM?
We have found that cells isolated from patients with brain tumour glioblastoma multiforme (GBM) have increased expression of the cell survival factor BCL6. BCL6 seems to contribute to the notorious resistance of GBM to radiation and chemotherapy, which leads to the poor prognosis for people with this disease. We will use primary GBM cells isolated from patient tumours and tumour models in mice to determine whether BCL6 inhibitors can increase sensitivity to the current therapies available for these patients, radiation and temozolomide chemotherapy. This study could lead to new treatment regimens for people with GBM
A randomised phase II/III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer - TOP GEAR: Trial Of Preoperative therapy for Gastric and Esophagogastric junction Adenocarcinoma (phase III component only).
TOPGEAR is a very important trial. This trial will find out if stomach cancer patients live longer if they have chemoradiotherapy before surgery. 632 patients from NZ, Australia, Europe and Canada will go into this trial. Patients will receive either:
1. The current standard treatment - chemotherapy then surgery then further chemotherapy
2. The possibly better treatment of chemotherapy then chemoradiotherapy then surgery then further chemotherapy
If we find out that patients live longer if chemoradiotherapy is added in before surgery then chemoradiotherapy will become the standard treatment used in stomach cancer worldwide.
Targeting the epigenetic changes that control hypoxia-dependent epithelial to mesenchymal transition.
The blood vessels that supply tumours are underdeveloped and this results in regions of low oxygen (hypoxia) forming within the tumour. Hypoxia causes cancer cells to become more aggressive resulting in the spread of disease which leads to poor patient survival rates. This occurs because some enzymes that control gene expression require oxygen. During hypoxia these enzymes cannot function and this causes changes in the way that the cancer cell's DNA is organised, modifications termed "epigenetic". This work aims to identify and characterise key epigenetic changes that occur during hypoxia and understand how these changes cause cells to become invasive.
Targeted delivery of raloxifene nanomedicine as a new therapeutic strategy for the treatment of castrate resistant prostate cancer.
The survival of patients with castrate resistant prostate cancer is less than 33% over five years. Studies have highlighted the potential of raloxifene, a drug currently used for the treatment of breast cancer, in the control and treatment of prostate cancer. However, raloxifene is rapidly metabolised. To enhance the efficacy of raloxifene, we have encapsulated the drug in a nanomedicine carrier. Preliminary data show the superior toxicity of the nanomedicine containing raloxifene against prostate cancer cells. In this proposal, we aim to incorporate tumour homing properties to further enhance the nanomedicine that we have developed.
To attend the 27th Annual Lorne Cancer conference; 12-14th February 2015; Mantra Lorne, Lorne, Victoria, Australia
To undertake two post-graduate papers through Massey University
To Visit Professor Ari Melnick's lab, which is based at Weill Cornell Medical College in New York, and to attend the AACR run conference Advances in Brain Cancer Research Washington D.C. April 2015
To attend the 4th International Public Health and Palliative Care Conference, Bristol, UK, May 2015
Melanoma Summit 2015: Genesis Oncology Trust Sponsorship.
New Zealand health professionals will gather in Auckland on 6-7 November 2015 for the fourth national Melanoma Summit. The two-day multidisciplinary meeting will provide a unique and important opportunity to highlight recent developments and identify priorities for action for New Zealand. New Zealand melanoma rates are amongst the highest in the world. This two-day Summit will provide an opportunity for health professionals working in melanoma control to address ways to reduce its incidence and impact. The Summit will feature New Zealand and overseas experts recognised internationally for their contribution to melanoma control, and workshops on prevention, diagnosis, clinical management and research.
Building knowledge transfer and innovation in palliative care: Visit of international expert Professor Philip Larkin.
In the next fifteen years, the demand for palliative care is expected to increase by 24%. For New Zealand to meet this need, it is important that palliative care provision is future-proofed with services responsive to need and specialist doctors and nurses delivering care. Learning from how other countries have addressed such challenges are important. Professor Philip Larkin is internationally known in palliative care. In this ten day visit to Wellington, Professor Larkin will talk with a wide range of clinical and academic palliative care communities to discuss how high quality models of palliative care and partnership can be developed.
Sponsorship for Engineering & Physical Sciences in Medicine Conference 2015.
The Engineering & Physical Sciences in Medicine Conference is the preeminent conference concerning medical physics in Australasia, in 2015 being hosted in Wellington. A major focus of the conference is the application of medical physics to the diagnosis and treatment of cancer, with approximately 75% of the 300 delegates working in this field contributing to the cancer care team. A leading international expert will be brought to Wellington to participate as a keynote speaker. The keynote speaker will lead discussion in their specialist area bringing leading research, development and clinical practice to New Zealand.
Genesis Oncology Trust palliative care breakfast lecture series.
Now in its 11th year, the Genesis Oncology Trust Lecture Series continues to provide an easily accessible palliative care education opportunity. Delivered via teleconference, the eleven lecture series is attended by approximately 400 people each month. Registered sites throughout the country participate in the series. Participant numbers have seen more than 2300 people listen to the breakfast lectures to date in 2014.Thanks to the generosity of the Genesis Oncology Trust the lectures will continue to be available without charge to registered participants in 2015.
Printing of the revised edition of The Palliative Care Handbook.
The Palliative Care Handbook is a guide for clinical management and symptom control and an invaluable resource for healthcare professionals throughout New Zealand. This easy to use guide gives uncomplicated explanations of how to manage general and complex symptoms in patients with palliative needs. The Handbook is provided free of charge to healthcare professionals – predominantly doctors and medical students in all areas where palliative care happens; it gives confidence to those who use it and therefore improved patient and whanau experiences and outcomes. Around 80% of people using hospice services have terminal cancer. Providing education, resources and guidance in current best practice is essential to delivering the highest standard of care possible to patients, families and whanau.
A tool for risk profiling and accurate prognostication in paediatric glioma integrating clinical features with epigenetics – It is time to move on from the binary classification.
Paediatric glioma is the most common group of brain tumours in children. It comprises a large number of different tumours and it has been difficult to determine individualised treatments for many patients. Cutting edge molecular techniques have revealed new information about these tumours that has not been known before. The difficulty is how to bring these new technologies in the clinic room to decide treatment. This project looks to combine clinical information with information from these new techniques to decide exactly how all this information fits together to form the best treatment for children with glioma.
Targeting tumour hypoxia for precise and personalised treatment of head and neck cancer.
The proposed research focuses on exploiting hypoxia (low oxygen) for treatment of head and neck squamous cell carcinoma (HNSCC). There is compelling clinical evidence suggesting that hypoxia contributes to aggressive disease and failure of ‘standard-of-care' chemo-/radiotherapy in HNSCC. Developing therapeutic strategies to destroy hypoxic tumour cells is therefore a high priority for improving clinical outcomes for HNSCC. Hypoxia-targeting drugs discovered in NZ show great promise for treating this disease. The proposed research aims to characterise determinants of tumour sensitivity to these compounds in order to enable prospective identification of HNSCC patients whose disease is sensitive to hypoxia-targeting drugs.
Studying the contribution of secondary tumor suppressor gene mutations to AML1-ETO driven acute myeloid leukaemia (AML) in a murine bone marrow transplantation model.
Acute myeloid leukaemia (AML) is an aggressive type of blood cancer. This disease is mainly driven by a number of changes (mutations) in the genetic material of certain white blood cells. Several recent studies have identified frequently mutated genes in AML patients, but the actual contribution of these genes to the disease is currently not known. We want to study the impact of these mutations on leukaemia development in a mouse bone marrow transplantation model. This will help us to identify pathways that might be targets for future therapies and thereby might significantly improve patient quality of life and survival.