Overview of research initiatives
The major research areas that have received support from the Foundation are notably:
Arrow/HCC Research Scientist 2016 Report
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.
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 Hematopoietic Stem Cell Transplant (HSCT) can be significant, but a successful telehealth programme pilot conducted by Professor David Ma in 2013 has found that improved outcomes can be achieved for autologous and allogeneic HSCT patients using telecommunication technology to receive supervised exercise training and stress management programs.
The pilot study demonstrated the feasibility of the programme, providing evidence of improvements in physical strength, cardiovascular fitness, aerobic fitness, subjective wellbeing and reduced levels of fatigue and distress without unduly increasing cost, time and travel burdens.
The project, titled: Adoption and sustainability of a telehealth treatment program to improve the health of cancer survivors after Hematopoietic Stem Cell Transplant (HSCT), aims to improve outcomes for HSCT patients at 1-6 years post-transplant and targets patients who are within the medium-term post-transplant period.
With support from a generous private donor, Arrow has contributed an additional $50,000 to the programme, bringing the total donated to $130,000. The programme has also received $50,000 from the St Vincent's Hospital Clinic Foundation. If successful, the outcomes may be adapted to meet the needs of other cancer survivors, individuals with chronic diseases and solid-organ transplant survivors.
Arrow contributes $33,469 to the CCIA / ABMTRR cancer after stem cell transplantation (CAST) study: adult cohort
The Children's Cancer Institute Australia (CCIA) is collaborating with the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) to conduct the cancer after stem cell transplantation (CAST) study part funded by Arrow.
In Australia, approximately 4000 adults were recipients of allogeneic haematopoietic stem cell transplantations (HSCT) between 1992 and 2007. While long term survival for adults treated with HSCT has increased, new malignancies have proven to be a significant late effect.
Arrow will provide a $33,469 grant to the ABMTRR in support of the second phase of the study which links a collection of transplant risk factor data to provide unbiased estimates of the incidence and risk factors for survival and new malignancies for recipients of allogeneic HSCT.
The approximate 350 adults who undergo allogeneic HSCT each year will benefit in terms of their clinical management and follow-up. Given that malignancy is the most significant late complication of HSCT, the study will provide impartial estimates of the incidence and risk factors for survival and new malignancies in the Australian population.
The project involves two stages:
Part one, near completion and fully funded by the National Health and Medical Research Council (NHMRC), involves data linkage of this population with the National Death Index and the Australian Cancer Database to obtain survival data and new malignancies.
Part two involves medical record abstraction at all Australian allogeneic HSCT units to enhance transplant risk factor data currently held by the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR).
Although it is accepted that the burden of new malignancies in allogeneic HSCT recipients is increased relative to the general population, there is no population-based data and no consensus on the types of cancers that are increased. Australia is in an internationally unique position to conduct population-level research due to the comprehensive coverage of the national death and cancer registries and the cancer types found to be increased will be specific to an Australian population.
Arrow is pleased to support this study which aims to demonstrate: the overall and site-specific incidence rates of new malignancies occurring in recipients of allogeneic HSCT; the overall and cause-specific mortality rates of recipients of allogeneic HSCT, and to evaluate the risk factors of new malignancies occurring in recipients of allogeneic HSCT.
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.
By Professor David Ma, Director, Blood Stem Cell and Cancer Research Programme, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney.
The annual Light the Night (LTN) charity benefit concert has provided vital morale and financial support to research projects at the Department of Haematology and Bone Marrow Transplant, St Vincent's Hospital, Sydney, since 2004. For research in the field of blood and marrow transplants, the LTN grant has allowed us 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. Acute leukaemia is not a single disease and existing tests are unable to separate them, thus hindering development of new treatments. Understanding the molecular pathology of acute leukaemia will provide new diagnostic tests and target specific drugs.
The invention of gene chips and other technological advances during this period has allowed us to examine changes in thousands of genes in cancer cells simultaneously. We have been able to discover several critical abnormalities unique to specific types of acute leukaemia. In the study of acute lymphoblastic leukaemia, our team has discovered a new cell signal pathway that links to resistance of leukaemia to treatment.
The second discovery we have made is that microRNAs, small gene switches, promote survival of acute myeloid leukaemia cells. We are currently performing clinical studies to see if these small gene switches could be used to predict patient response to treatment. Experiments are underway in our laboratory to discover new drugs that may one day be used in the clinic. During this period, our unit has trained a number of budding scientists and young doctors advancing their career and contributing to leukaemia research.
Our scientific breakthroughs have been internationally recognised as important contributions in this research field. Summing up, these achievements would not be possible without the generous backing of the dedicated organisers, artists and supporters of the annual LTN Benefit Concert and our ultimate goal is to cure leukaemia without chemotherapy - something Matt Rennie would be proud of.
Written by Associate Professor Claire Vajdic
With the generous support of Arrow donors, a multidisciplinary team of researchers has 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. The paediatric paper was recently accepted for publication in the prestigious international journal Leukemia, and two other papers describing the adult cohort have already been published in other international journals.
For the most recent publication, the investigators studied 717 children who received an HSCT at an Australian children's hospital between 1982 and 2007. The median age at transplantation was 7.6 years (range 0.3-14.5) and more than 50% of patients received HSCT therapy for acute lymphoblastic leukaemia (ALL). For most patients, stem cells were sourced from matched, related donors and HSCT conditioning incorporated total body irradiation and the drug cyclophosphamide.
Records from hospitals and the Australasian Bone Marrow Transplant Recipient Registry (the ABMTRR) were linked with routinely collected cancer and death records. This linkage identified second cancers in 17 transplant recipients and 44 deaths more than two years after transplantation. A second malignancy was most likely to be diagnosed 5 to 9 years from HSCT, and most second cancers were diagnosed in patients who had received total body irradiation.
Children who have had HSCT should undergo regular clinical check-ups and blood tests to monitor for relapse and complications of therapy. When cancers are diagnosed early, there are more options for treatment and the outcomes are superior. These findings support the active surveillance of patients considered high-risk for thyroid cancer in particular as this cancer can be asymptomatic. Behaviours that are known to increase cancer risk, such as smoking and alcohol use, poor diet and lack of exercise, should be avoided.
This is the largest study of this kind to-date and the findings are consistent with previous single-transplant centre studies. It shows that pediatric patients undergoing transplantation are at risk of second cancer and late mortality, although the total number of affected patients is low. Furthermore, 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.
With the generous support of our donors, a Panasonic Multigas incubator (Low Oxygen incubator) and ThermoFisher Savant (SpeedVac) have been purchased for the medical research team at the Blood Stem Cell and Cancer Research Unit, St Vincent's Hospital, Sydney. Arrow supporters contributed $15,000 to the acquisition of the Oxygen incubator, and a $13,000 grant from Allens, a leading international law firm, enabled the purchase of a SpeedVac for the research team. Both pieces of equipment will ultimately help to improve bone marrow transplant outcomes for patients.
Severe degenerative intervertebral disc (IVD) disease is an incurable condition and a major cause of harsh back pain. It has been demonstrated that human bone marrow stem cells (BMSCs) can survive when transplanted into the IVDs of rodents.
Researchers from the Blood Stem Cell & Cancer Research Unit at St Vincent's Hospital, Sydney, and the Orthopaedic Research Institute, St George Clinical School, UNSW, have also shown that these disc like cells can be generated from BMSCs in culture flasks.
As it is Arrow's mission to foster research into diseases treatable by bone marrow and stem cell therapy, a funding grant of $40,000 has been approved by Arrow's Executive Committee to support this very promising research project which 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 programme and hopes to benefit thousands of patients with severe lower back pain.
2014 Project update:
Acute Myeloid Leukaemia (AML) is an aggressive type of blood cancer that can affect children and adults. The exact mechanism of how normal bone marrow cells transform into leukaemic cells remains a major hurdle in discovering a cure for this cancer. Abnormal changes in small regulatory genes called microRNAs have been found in many cancers. Our recent research supported by LTN using gene chip technology discovered unique abnormalities in microRNAs in AML. One particular gene called miR-10a was studied in more detail in our research. We found that certain AML cases have extremely high levels of this gene. Exciting experiments performed by Dr Catalina Palma and medical student Hons candidate Joel Tan showed that miR-10a is a survival gene for leukaemic cells and inhibiting miR-10a leads to the death of leukaemic cells. Dr Thanh Vu the Arrow BMT Foundation research scientist has identified the possible mechanism controlling miR-10a expression. Working in collaboration with a leading research team in Germany, miR10a has been found to be a potential biomarker for this type of AML. We are expanding this study into a larger cohort of patients and planning to use animal models in the near future for drug testing against AML. The goal is to discover a new class of diagnostic tests and new non-chemotherapy drugs to treat patients with leukaemia. On behalf of our research team, I would like to thank the members of LTN organizing committee, LTN volunteers and supporters for providing invaluable funds to continue our research goal to find a cure for leukaemia.
By Professor David Ma, Director, Blood Stem Cell and Cancer Research Programme, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney.
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.
Arrow continues to support high research standards at the Blood Stem Cell and Cancer Research Unit, Department of Haematology & Bone Marrow Transplantation, St Vincent's Hospital, Sydney, through the funding of critical medical equipment.
In 2011, the Hawkesbury Canoe Classic (HCC) generously funded Arrow's purchase of the following pieces of medical research equipment for the Blood Stem Cell and Cancer Research Unit, Department of Haematology & Bone Marrow Transplantation, St Vincent's Hospital, Sydney (SVH):
Research into the early detection, better treatments and ultimately a cure for leukaemia depends on accuracy and precision, so Arrow supporters also contributed to the purchase of a Pipette Set for the precise handling of liquids used in research.
When peripheral blood stem cells (needed for transplant) are collected on the Cobe Spectra machine, they need to be separated from the collection kit in a sterile fashion. A 'heatsealer' achieves this and ensures the stem cells are viable for transplant. With the generous support of Michelle Hilton-Vernon and John Vernon, Arrow has purchased the first of the latest model to be released in Australia and has donated it to the Bone Marrow Transplant Laboratory at St Vincent's Hospital where 71 peripheral blood stem cell collections were performed last year. The new model is smaller and more lightweight than previous models.