Arrow is the only national charity dedicated to helping medical researchers find better treatments for blood cancers like leukaemia, blood disorders and autoimmune disease (such as Multiple Sclerosis) that are treatable by bone marrow and stem cell therapies.
Our primary objective is to support grass-roots research and we have often been the first funders of medical research that has gone on to receive larger foundation or government grants.
The key areas of research we have funded include:
- Graft-versus-host-disease (the major cause of death in post-transplant patients).
- Bone marrow stem cell biology and its potential clinical applications.
- Molecular biology of leukaemia and lymphoma.
Our past and present research projects include:
The Arrow/HCC Research Scientist grant in 2019 enabled Dr Tim Molloy to contribute to the exciting new research in the Department of Haematology’s Blood, Stem Cell and Cancer Research Program at the St Vincent’s Centre for Applied Medical Research of St Vincent’s Hospital Sydney. Anaemia (insufficient red blood cells) is a prevalent disorder, affecting more than 10% of adults over 65, and >15% over age 75. Anaemic patients are at risk of impaired cognitive and physical functions, cardiovascular disease, hospitalisation, and high mortality, therefore represents a major health and economic burden in Australia. Strikingly, the causes of anaemia are unknown in up to one third of patients. The diagnosis of unexplained anaemia (UA) is made after protracted investigations and they are also difficult to treat effectively. Actionable tests and effective drugs for UA are therefore urgently needed. We postulated that most cases of UA could be explained by the acquisition of aging associated gene mutations in blood cells similar to myelodysplasia (MDS). Our research study of over 200 patients attending the two local outpatient clinics was amongst the first to address this hypothesis by applying ultra-sensitive “deep next-generation sequencing” technology. Gene mutations identified in the blood cells of each patient were then correlated to the incidence of cytopenia, including UA. We observed that the prevalence of blood gene mutations were increasing with advancing age. Importantly, patients with unexplained anaemia have more recurring mutations than non-anaemic patients which supports our initial hypothesis that specific blood mutations may be driving this disorder. These exciting discoveries are a strong indication that these aging associated genetic changes may be key factors leading to UA. Our plan is to undertake further investigations using advanced pre-clinical laboratory models to uncover how these mutations may alter the bone marrow stem cell functions resulting in anaemia. The goal is to develop new diagnostic test and to create new drugs to patients with unexplained anaemia. These new discoveries may also help the management of BM transplant patients.
Dr Tim Molloy, a conjoint Senior Lecturer at the University of New South Wales, has continued his commitment to mentoring young scientists, supervising an honours student in 2019 and a new PhD student, Halla Eyjolfsdottir from Iceland who has joined our research program in mid-2019.
Project outline by Professor David Ma and his team at the Blood Stem Cell and Cancer Unit at St Vincent’s Hospital, Sydney.
In the last few years several international publications have reported that within the general population of people with normal blood counts, greater than 5% over 60 years of age have acquired abnormalities (mutations) in genes associated with blood cancer, such as myelodysplasia and acute myeloid leukaemia. These studies have identified that (1) the percentage of individuals with these mutations increase with age from less than 1% for age less than 40 to over 10% for age above 80, and (2) these individuals have a 10-fold higher risk of developing myelodysplasia or leukaemia.
The contribution of these mutations toward development of malignancy depends on the individual mutations and the interactions with other factors in an individual. Some of these mutations may be the key factor initiating the transformation of normal bone marrow cells to become pre-cancerous and then cancerous, while others promote survival or expansion of these abnormal cells. The precise role of these abnormal genes in disease evolution from normal ageing stem and progenitor cells to pre-cancer and then cancer cells remains to be determined. Recent advances in technological capabilities have made this determination possible, and this is the goal of the current project.
The aims of our team are:
(1) to identify the variety and frequency of acquired myeloid gene mutations in the blood of several hundred subjects from the general public involved in large Australian population studies, using state-of-the-art Next Generation Sequencing techniques;
(2) to correlate these aging-associated gene mutations with subjects health and disease outcome over time, particularly altered and malignant blood cell development such as anaemia, cytopenia, myelodysplasia and other blood cancers;
(3) to determine which mutations may be predictive of disease development, and may therefore be targets for closer monitoring of patients, or potential drug targets to prevent or treat disease progression.
To achieve this goal, we are (1) in the process of establishing a highly skilled and focused team of researchers devoted to this project, (2) extending existing collaborations with the SVHS geriatric department to 3 other national centres to recruit sufficient numbers of cases essential for the success of this project, (3) in partnership with an Australian pharmaceutical company (Phebra) to fund a sub-study of this project, (4) setting up collaborations with other medical and non-medical researchers including mathematicians and statisticians to address scientific issues related to big data studies, (5) planning to apply for research funds pending on results generated to ensure completion of the aims of this project.
Dr Melinda Tursky has a great passion for working in the field of normal and malignant human blood stem cell research and has brought her research expertise to the Blood Stem Cell and Cancer Research Programme, St Vincent’s Centre for Applied Medical Research soon after completion of her PhD. The research for her PhD was on understanding of the role of a gene called Erg in the progression from normal to cancerous blood cells. Melinda has presented her work at national and international conferences, and has publications in the top Haematology journals. She also has several years of experience in private industry in the development of blood stem cell culture systems for clinical applications.
As the Arrow/HCC Research Scientist, her project utilises cutting edge technology of stem cell reprogramming and gene editing to identify genetic changes which drive the progression of normal cells to acute leukaemia. Genetic mutations are commonly found in leukaemia, but for many leukaemias it is unclear which mutations are crucial to cancer progression. Melinda’s work utilises reprogrammable ‘induced pluripotent stem cells’ (iPSC) derived from skin or blood cells of people with normal blood cell development and people with altered blood cell formation due to genetic changes, such as children with Down Syndrome who have a much higher risk of developing leukaemia than other groups. In this last 12 months, due to the tremendous efforts of Melinda and To Ha, the previous Arrow Research Scientist, our team has developed optimal methods for turning iPSC into blood cells. Melinda is currently gathering data in preparation for publication that will contribute significantly to this rapidly developing field. The next step will use targeted gene editing to introduce mutations or to correct genetic alterations to identify which changes drive leukaemic progression.
Dr Melinda Tursky joined the Blood, Stem Cell, and Cancer Research (BSCCR) Programme, at the St Vincent’s Centre for Applied Medical Research, Sydney in 2015 after completion of her PhD at the Prince of Wales Clinical School, Faculty of Medicine, UNSW Australia.
This study assesses the efficacy and safety of performing haploidentical (half-matched) transplants using myeloablative or full dose chemotherapy, to reduce the risk of graft vs host disease for patients who do not have a matched donor.
The data will be captured using a new online database associated with the Australasian Bone Marrow Transplant Recipient Registry.
A phase II trial of haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide as GVHD prophylaxis by Dr. John Moore.
Haemopoietic stem cell transplantation (HSCT) is a procedure often used to cure malignant blood conditions. HSCT can cure blood tumours by using the donor’s immune system to kill residual tumour cells that are left in the body of a patient after chemo or radiotherapy (conditioning). This benefit of potential cure is unfortunately offset by a complication called graft versus host disease (GVHD) where the donor’s immune system attacks the patient. For this reason, HSCT has been limited to people who have a donor matched to them via proteins on the surface of cells that are inherited from our parents called the HLA system. Most transplants are performed using a matched sibling donor (where there is a 30% chance one of the patients’ siblings will be matched) or an unrelated donor (from transplant registries around the world). HLA matched is considered when 8/8 proteins are the same in the patient and donor. This unfortunately leaves about 20% of patients with blood tumours who don’t have a sibling or unrelated donor. Often these patients have been excluded from the potential of a cure from a transplant because they are considered not to have a donor.
One potential for these patients is to use a family member (usually a parent or child) who is half matched or 4/8 HLA proteins. This type of HSCT is called a haploidentical transplant. Until recently this type of transplant was generally very dangerous because of the increased risk of GVHD due to the difference in the immune system of a donor and recipient (who are only half matched). Recent research by Chinese and American groups has shown that if you use an old and cheap chemotherapy drug called cyclophosphamide after stem cells have been infused into the patient, GVHD can be prevented without affecting the infused stem cell or the immune attack on the blood tumour. This type of transplant has been performed in several units in Australia using minimal chemotherapy to kill off the tumour – so called reduced intensity conditioning (RIC) transplants.
This study aims to assess this new way of performing haploidentical transplants using myeloblative or full dose chemotherapy in patients whose leukaemia needs the maximal amount of treatment. This study plans to use either Busulphan or total body irradiation as the full dose of treatment to ablate or remove the patient’s bone marrow prior to giving back the haploidentical stem cells from the donor. There have only been a few studies using this procedure in medical literature, but is it known from conferences that many units are looking at the same procedures to help the 20% of patients who don’t have donors. Safety and the efficacy of haploidentical HSCT are the main issues that will be assessed in this trial and it is anticipated that all the data can now be captured using a new online database associated with the Australasian Bone Marrow Transplant Recipient Registry.
The physical and psychological risks that follow a stem cell transplant can be significant. Using telecommunication technology to deliver supervised exercise training and stress management programs during the recovery period can deliver considerable improvements in patients’ physical strength, cardiovascular fitness, aerobic fitness and wellbeing, with minimal cost, time and travel burdens.
Arrow has contributed a total of $130,000 to the program, which has also received $50,000 from the St Vincent’s Hospital Clinic Foundation.
The Children’s Cancer Institute Australia is collaborating with the Australasian Bone Marrow Transplant Recipient Registry to conduct this cancer after stem cell transplantation study, part-funded by Arrow.
Arrow provided a $33,469 grant to the ABMTRR in support of the second phase of this study, which aims to:
- Demonstrate the overall and site-specific incidence rates of new malignancies occurring in recipients of stem cell transplants.
- Demonstrate the overall and cause-specific mortality rates of recipients of stem cell transplants.
- Evaluate the risk factors of new malignancies occurring in recipients of stem cell transplants.
The Children’s Cancer Institute Australia (CCIA) conducts world-class research into the causes, diagnosis and treatment of cancer, with a particular emphasis on paediatric cancers
The annual Light the Night (LtN) charity benefit concert provided vital morale and financial support which was directed to research projects at the department of haematology and bone marrow transplant at St Vincent’s Hospital, Sydney.
The LtN grant allowed the hospital to develop a new molecular test to monitor accurately the success of donor stem cell transplants.
Despite improvements in treatment of acute leukaemia in the last few decades, it remains a potentially fatal disease and incidence is on the rise in our society. Understanding the molecular pathology of acute leukaemia will provide new diagnostic tests and target specific drugs.
The hospital’s scientific breakthroughs have been internationally recognised as important contributions in this research field.
With the generous support of Arrow donors, a multidisciplinary team of researchers examined the risk of second cancers and late mortality in Australian children treated by allogeneic haemopoietic stem cell transplantation (HSCT) for a blood cancer.
This was part of the Cancer After Stem Cell Transplant (CAST) study, which also received funding from the NH&MRC. This was the largest study of this kind to date and the findings were consistent with previous single-transplant centre studies.
The study showed that paediatric patients undergoing transplantation are at risk of second cancer and late mortality, although the total number of affected patients is low. Radiation conditioning procedures have been optimised over time to maximise the safety of HSCT and HSCT remains a life-saving therapy for children with blood cancers.
We are committed to supporting high research standards at the blood stem cell and cancer research unit at St Vincent’s Hospital, Sydney. Thanks to our generous supporters we’ve been able to donate the following equipment to the unit’s medical research team:
- A Panasonic multigas incubator (low oxygen incubator) and ThermoFisher Savant (SpeedVac).
Arrow supporters contributed $15,000 for the oxygen incubator and a $13,000 grant from Allens, a leading international law firm, enabled the purchase of the SpeedVac. Both pieces of equipment will ultimately help to improve bone marrow transplant outcomes for patients.
- In 2011, the Hawkesbury Canoe Classic (HCC) generously funded Arrow’s purchase of the following pieces of medical research equipment:
- A dissecting microscope
- Minus 80° freezer
- Refrigerated benchtop centrifuges
- Cytospin centrifuges
- Low temperature incubator
- A ‘heatsealer’, used to separate peripheral blood stem cells collected on the Cobe Spectra machine from the collection kit, was purchased with the generous support of Michelle Hilton-Vernon and John Vernon.
This research uses a novel approach to recreate leukaemia from Down Syndrome stem cells in the laboratory and aims to trace step-by-step the molecular circuitry/pathways involved in the development of blood cancer and hopefully identify candidate targets for new drug discovery.
Trisomy 21 by Professor David Ma
Acute leukaemia is the number one cause of cancer in children. Sadly, one in five babies born with Down Syndrome (DS, Trisomy 21) develop abnormal blood cells at birth, which can evolve into acute leukaemia in 20% of these infants. This occurrence rate is 500 times higher compared to the age-matched general population. Current treatment has significant side effects and is stressful for the child and their family. Although the extra copy of chromosome 21 in Down Syndrome is linked with the increased risk of getting leukaemia, genetic defects on other chromosomes would likely play a role in the development of leukaemia. Indeed mutations of key genes that regulate blood stem cell growth and development, like GATA1 and TP53, are frequently identified in Down Syndrome leukaemia children. Precisely how these genetic defects work with each other to cause acute leukaemia remains unclear.
Our research uses a novel approach to recreate leukaemia from Down Syndrome stem cells in the laboratory. Using a cutting edge molecular biology method invented a few years ago by Japanese researchers, we have been able to convert Down Syndrome skin cells into a renewable source of embryonic-like stem cells known as induced pluripotent stem cells (iPSCs). In our further experiments, we were able to direct these iPSCs to form blood stem cells (CD34+) and then mature blood cells. Interestingly, we found Down Syndrome iPSCs produced significantly more blood cells compared to control cells. These exciting findings suggest that our iPSC culture system can reproduce the abnormal development of blood cells expected in these infants and could be used to investigate the cancer causing genes leading to Down Syndrome leukaemia.
Our next step is to use gene editing technology on our iPSCs to test which one of the suspected cancer causing genes will transform the blood cells to become cancerous. In doing so, we will be able to trace step by step the molecular circuitry/pathways involved in the development of blood cancer and hopefully identify candidate targets for new drug discovery.
Severe degenerative intervertebral disc (IVD) disease is an incurable condition and a major cause of harsh back pain. It’s been found that human bone marrow stem cells (BMSCs) can survive when transplanted into the IVDs of rodents – and researchers at St Vincent’s Hospital, Sydney and St George Clinical School, UNSW have also shown that these disc-like cells can be generated from BMSCs in culture flasks.
Arrow provided $40,000 to support this very promising research project that is now at the exciting stage of transplanting the disc-like cells into rodents to test their potential to repair damaged IVDs. This new study is part of an adult stem cell program and hopes to benefit thousands of patients with severe lower back pain.
Nurses and dietitians caring for people post-transplant have noted in their clinical work that despite the current management, patients who receive autologous and allogeneic bone marrow transplants (BMT) are still reporting nausea and vomiting for prolonged periods of time. It is commonly observed that patients require medication for nausea, to a lesser extent vomiting, up to six months post-transplant and sometimes longer, resulting in readmission to hospital and decreased quality of life for patients. These symptoms may interfere with nutritional balance, the ability to take oral medications and often inhibits weight gain resulting in an increased susceptibility to adverse outcomes such as infection and renal damage.
With support from the Hawkesbury Canoe Classic (HCC), Arrow is pleased to provide funding for a research assistant for a project that seeks to establish whether prolonged nausea and vomiting following BMT has previously been reported in literature. If there is no research that reports this, it is likely that a gap exists that will need to be explored. A nurse-led multidisciplinary group of transplant clinicians at Liverpool Hospital is identifying research that may be used to develop practice guidelines, which could extend beyond the project team’s local networks.
Findings from the project will assist clinical staff caring for bone marrow transplant patients in understanding more about the duration and severity of nausea and vomiting post autologous and allogeneic bone marrow transplant. This will enable staff to recognise and manage nausea and vomiting more effectively using an evidence based approach.