Research

CLCRF Researchers head overseas to extend their knowledge

Two of The Children’s Leukaemia and Cancer Research Foundation’s top researchers attended conferences in North America and Europe to continue their studies in both acute lymphoblastic leukemia (ALL) and the bone marrow microenvironment during leukaemogenesis.

Dr Laurence Cheung attended a very important Keystone conference ‘Keystone Symposia: Novel Aspects of Bone Biology’ in June 2018 in Salt Lake City. Attendance at this conference has reaped many dividends in terms of new collaborations and networking for the Microenvironment project as well as learning new insights regarding the bone marrow microenvironment during the development of leukaemia. Dr Cheung also presented a poster at the conference.

In May this year, Dr Rishi Kotecha attended the iBFM and CLLS conference in Helsinki, Finland. This conference is by invitation only and one of the specific benefits included meeting TKI’s research laboratory collaborators from the Karolinska Institutet to further develop one of the iALL projects in progress.

Acute lymphoblastic leukaemia (ALL) is a type of cancer that affects the blood and bone marrow. ALL is characterised by an overproduction of immature white blood cells, called lymphoblasts or leukaemic blasts.

CLCRF funded both of these travel grants to the conference.

CLCRF Funds Research to Slow Down Leukaemia in Children

Dr Rishi Kotecha, one of the scientists at the Perth Children’s Hospital, is leading the way in research, funded by the Children’s Leukaemia & Cancer Research Foundation Inc. This research has unlocked a vital key to slow down the progression of leukaemia in children.

The journey for a child with cancer is not a straightforward one, and has many ups and downs. Dr Rishi Kotecha says it’s wonderful when he hears from patients many years later who are well again, graduating from university or starting families of their own. At times his job has difficult moments such as discovering that the prognosis is not good for a young cancer patient. As a result, he is determined to discover new lifelines and better treatments that can lessen the suffering of children with leukaemia.

Working together with eight scientists, Dr Kotecha’s team of researchers at the Telethon Kids Institute, may have found a vital key that will slow down progression of leukaemia in children and has opened the door to a new way of thinking about treatment. These findings have been so significant that he and lead author, Dr Laurence Cheung, published them in the prestigious Nature journal, Leukaemia.

The researched looked at acute lymphoblastic leukaemia (ALL), which is the most common cancer among children, and a specific type called pre-B ALL.

More than a third of children with pre-B ALL have bone pain and skeletal defects at the time of diagnosis so the researchers wanted to know what was causing these symptoms.

“The bone pain at diagnosis can be quite severe,” adds Dr Kotecha, “not in all cases, but in a lot of cases there are aches, pain and fractures because their bones are brittle.”

The research team set to work by creating a highly aggressive subtype of pre-B ALL in their lab models.

They were able to identify a signal produced by the leukaemia cells which instructed cells in the micro-environment to eat away at the bone.

Desperate to find out how to stop those bone-eating cells wreaking further carnage, they tried using a commercially available drug called zoledronic acid.

The drug, which was already known to be safe for children, was a game changer.

Not only did it help reduce bone fragility, it slowed the advancement of the cancer.

Sadly, Australia was found to have one of the highest rates of leukaemia in the world. The survival rates have dramatically improved over the past 60 years but it is still one of the most common causes of cancer-related death in young people.

One of Dr Kotecha’s patients, Xander Thelan, is today the picture of health. So it is hard to believe that this 10-year-old Perth boy underwent three-and-a-half years of gruelling chemotherapy to treat leukaemia and benefited from taking part in clinical trials using a novel drug that came about from the research findings.

Xander was only five when he was diagnosed with leukaemia. Thanks to clinical trials coming from this key research, Xander finished chemotherapy last year and is now doing well.

The Telethon Kids Institute is working at a local, national and international level to try to further understand leukaemia and find and test new treatments such as this one.

“We just feel so lucky to live in Australia, in a country with such good health care and the research that they’re doing, because it is world class,” says Xander’s mother, Naomi Kerp.

“It was a wonderful feeling and it’s such a long road, three-and-a-half years of chemotherapy, that when you reach the end it’s just this beautiful feeling that it’s finally over.”

Dr Kotecha says that happy outcomes such as Xander’s continues to drive him.

The CLCRF is proud to fund international class research by scientists such as Dr Rishi Kotecha, Dr Laurence Cheung and their team that leads to better outcomes for children with cancer.

Photo taken by: Iain Gillespie

Dr Sébastien Malinge Investigates Resistant Cancer Cells

French scientist, Dr Sébastien Malinge, moved from Paris to Perth six months ago to work as an Ursula Kees Fellow. He now works in a lab funded by the Children’s Leukaemia & Cancer Research Foundation within the Telethon Kids Institute. Sébastien is enjoying his time in Perth and continues his insightful research into better therapies for children who have leukaemia. We interviewed Sébastien on 12 April at the Telethon Kids Institute to learn more about him and his research.

Sébastien’s PhD research in 2006 at the Necker Hospital in Paris was focused on discovering the genetic causes of leukaemia among children with Down’s Syndrome. Sébastien then moved to the United States to complete a post-doctoral fellowship to investigate why children with Down’s Syndrome were at higher risk of developing leukaemia than children without the condition. He moved back to Paris in 2012 to expand on what he studied.

When asked about what receiving the Ursula Kees Fellowship means to him, Sébastien says he feels privileged to receive this position.

“I met Ursula in 2016 when she invited me to present my work at the Telethon Kids Institute.

“I am very proud of having received this fellowship and continue to pursue her legacy. We work towards the same goal of finding better treatments for children with leukaemia.”

Sébastien is currently focusing on building a cohort of preclinical tools to test hypotheses with the view of testing new cancer therapies. He seeks to understand why some children relapse and the reason as to why some cancer cells are resistant to chemotherapy. He hopes that his research will give some clues to develop new therapies targeting therapy-resistant cancer cells and decrease the rate of relapse.

Sébastien believes that funding into cancer research is crucial for discovering better therapies.

“Some of these leukaemia treatments for children are successful but have high toxicity. Therefore, we need funding to find better ways to maximise the well-being of these children not only during but also after chemotherapy.”

Thank you Dr Sébastien Malinge for accepting the Ursula Kees fellowship. We are excited to have you on board and look forward to learning more about your research into finding better therapies for children with leukaemia.

CLCRF Scientists Discover Bone Density Treatment Slows Progression of Leukaemia

Researchers at the Telethon Kids Institute who are funded by the Children’s Leukaemia & Cancer Research Foundation (Inc.) have discovered a vital key to the progression of leukaemia in children. This finding has led to a paradigm shift in how researchers think about treating patients with leukaemia. The researchers have found that treating the cancer cells as well as their environment is key.

In new ground breaking research published in the Nature journal, Leukemia, by a team of scientists, including Dr Rishi Kotecha, led by Telethon Kids Cancer Centre researcher, Dr Laurence Cheung, documented how they have identified the mechanism of bone loss that occurred during the development of leukaemia. When the microenvironment around the leukaemia cells were treated, this was able to reduce the progression of leukaemia.

The findings, while still in the pre-clinical phase, are promising and suggest that targeting the microenvironment around leukaemia cells can help fight leukaemia and also provide relief for one of its most painful side-effects, bone loss.

Acute lymphoblastic leukaemia (ALL) is the most common cancer among children and common cause of cancer-related death in those under 20 years of age. Dr Cheung’s study focused on the most common form of leukaemia in children, a subtype of ALL known as pre-B ALL.

“When we created a pre-clinical model replicating this kind of leukaemia, we witnessed substantial bone loss during the development of the cancer,” Dr Cheung said.

“We went back to the literature and found that more than a third of children diagnosed with pre-B ALL had symptoms of bone pain and skeletal defects at the time they were diagnosed – suggesting leukaemia cells can alter their surrounding environment.”

The researchers wanted to discover what was causing the bone loss, and identified a signal produced by the leukaemia cells which instructed cells in the microenvironment – known as osteoclasts – to eat away at the bone.

“Then we thought, what if we stop the bone-eating cells from eating the bone away – will this have an impact on the development of leukaemia?” Dr Cheung said.

The team used a commercially available drug called zoledronic acid – already known to be safe for children and used to treat brittle bone disease – to target the cells in the microenvironment around the leukaemia cells.

“Importantly, we found that this not only compensated for the leukaemia-dependent bone fragility, but also reduced leukaemia progression,” Dr Cheung said.

He said although similar thinking had been applied previously to cancer in adults, the finding offered an exciting new treatment angle for children.

“To date, the main strategy for cancer therapy in children has focused on targeting malignant cells with chemotherapy, which is toxic for the leukaemia cells but also toxic for the patient.

“Our finding that the cells surrounding the leukaemia cells can contribute to treatment failure or success has led to a paradigm shift.

“It’s not going to replace chemotherapy, but we propose that using chemotherapy and treating the microenvironment at the same time will have more benefit than just the chemotherapy by itself.

“What it really shows is that it’s important to look at that whole picture, and not just the leukaemia cells, because the leukaemia cells and the cells in the surrounding microenvironment are all talking to each other.”

The next step of their study is to expand the research using a similar treatment on other sub-types of the same kind of leukaemia to see if a similar impact could be achieved and to ensure that zoledronic acid was compatible with current chemotherapy agents.

“There’s quite a way to go yet, but it’s exciting to think about the paradigm shift this represents for children’s leukaemia, as well as the dual benefits it offers: both slowing the progression of the leukaemia, and mitigating this really common and painful side effect suffered by children with leukaemia, and that is the bone loss,” Dr Cheung said.

The full paper, New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment, can be read here.

The CLCRF is proud to fund key groundbreaking research in leukaemia and look forward to further exciting developments. If you would like to give towards child cancer research please donate to the CLCRF.

Dr Rishi Investigates New Cancer Drug in the Fight Against Infant Leukaemia

Dr Rishi Sury Kotecha is one of the scientists conducting child cancer research at the Children’s Leukaemia & Cancer Research Foundation (Inc.) Lab at the Telethon Kids Institute. His expertise lies in preclinical and clinical leukaemia research and he is currently conducting studies into a key new drug called Blinatumomab. In the study, he will be examining whether the drug, Blinatumomab, can be safely added to the standard chemotherapy used to treat infants under 12 months of age with acute lymphoblastic leukaemia.

Blinatumomab is a form of immunotherapy and binds to both the leukaemia cells and T-cells, which are important in our body’s natural defence against infections, facilitating destruction of the leukaemia cells by the T-cells. Dr Rishi believes Blinatumomab is going to be a crucial drug in the treatment of acute lymphoblastic leukaemia in infants.

Until now, studies have shown that Blinatumomab is safe to use in older children and adults. Dr Rishi’s research is an early phase trial, which aims to see whether using Blinatumomab is safe and feasible for treating infants under 12 months of age.

Most babies with pre-B acute lymphoblastic leukaemia have a very poor survival rate due to a genetic abnormality, which is called a MLL rearrangement. Only 40 percent of babies with this abnormality survive beyond five years. For those under three months of age, there is only 16 percent survival. This highlights the desperate need for better therapies to improve their outcome. It is hoped that Blinatumomab will not only improve the outcome of these infants, but also enable reduction of conventional chemotherapy which is highly toxic to their fragile bodies.

When asked why Dr Rishi chose to specialise in paediatric haematology/oncology, he is very positive “I chose this specialty for the successes that have come from such research. When I receive emails and photos from a child I’ve treated telling me about their lives, such as starting university and having families of their own, I see the impact that research has made on their outcome and it makes it all worthwhile.”

The CLCRF is proud to fund cutting-edge research such as Dr Rishi’s that leads to better outcomes for children with leukaemia.

$3,000 for NUT Carcinoma Research Manuscript

$3,000 in additional funding from the Children’s Leukaemia & Cancer Research Foundation (Inc.) (CLCRF) was provided for publication of Dr Alex Beesley’s research manuscript into NUT Carcinoma. Originally, CLCRF provided $12,000 in funding for manuscript costs. Now a further $3,000 has been granted to Dr Beesley to enable the completion of his manuscript for publication.

Dr Alex Beesley, Honorary Research Fellow at the Telethon Kids Institute, together with Dr Anja Stirnweiss conducted a landmark study to study key features of one of the most hostile cancers, NUT Carcinoma. The study looked into the genetics behind NUT Carcinoma. NUT Carcinoma is a highly aggressive cancer and research into better therapies for patients of the cancer is desperately needed.

In the study, researchers have used a unique panel of NUT carcinoma samples to look for drugs that are more effective at fighting these tumours. In addition, they have analysed the genetic code of these samples, the first time that this has been done comprehensively for this disease.

The findings, recently published in the prestigious journal Oncotarget, provide a blueprint of what goes wrong in these cancer cells and the types of drugs that might be best for treatment in the future. Dr Beesley’s research provides hope for finding better therapies for children who suffer from NUT Carcinoma.

The CLCRF is dedicated to funding research that will better the lives of children who suffer from this terrible disease and is glad to help Dr Alex Beesley in his key research.

Professor Ursula Kees’ Farewell Letter

Dear Foundation Supporter,

I have dedicated 34 years of my life to studying infant cancer at the Children’s Leukaemia & Cancer Research Laboratory.

With a grateful heart, I say thank you to the Foundation and its supporters for bringing me from Switzerland to Perth and giving me the chance to lead the Laboratory. It is with some sadness, that I announce that I have come to the end of my time as one of the founding scientists of the Children’s Leukaemia & Cancer Research Foundation (Inc.) (CLCRF) Laboratory.

During these 34 years, I have been struck by one word to describe the effects of infant cancer: AGGRESSIVE. Cancer in children is not the same as adult cancer. An adult cancer patient will experience five to 30 years of life lost due to cancer and its treatment. A child who is under 12 months of age is likely to lose 67 years of life through cancer and its treatments.

Sadly, one in 500 Australian children will develop cancer before age 15. Childhood cancer is still the leading cause of death from disease for Australian children.

Our Laboratory team has contributed to a world-wide effort to find better therapies for our young cancer patients – with great outcomes. In the mid-eighties, many patients did not survive. Today, successful therapies are available for the majority of our young cancer patients.

Here is a big BUT. Some of our patients initially respond to the therapy they are given, but soon the disease is back. This is devastating for the patient, the parents and siblings, for the doctors and nurses and for the researchers. My desire to help children survive through this terrible disease has driven me and my team these 34 years. We search for answers to fight childhood cancer in the Laboratory to bring better therapies to the patient.

For each patient, a treatment plan is worked out. The length of therapy may be a few months or up to three years. A patient may receive one form of treatment or a combination, depending on what researchers have found to be the most effective in destroying the patient’s particular type of cancer cells.

The most common types of treatment are chemotherapy, radiotherapy and surgery. I started in the CLCRF Laboratory in 1984, at a time when a new treatment was talked about, called ‘bone marrow transplantation’. Dr Michael Willoughby, the specialist who diagnosed and treated childhood cancer patients at the children’s hospital, was a pioneer of this treatment. In what turned out to be a great collaboration, our Laboratory team was able to contribute to the Bone Marrow Transplantation Program at Princess Margaret Hospital. Many lives have been saved through this Program.

Some patients receive chemotherapy over three years – a very long time. For the first few weeks they are in hospital and afterwards they have to come to the children’s hospital for treatment – many times over three years.

They are given up to 12 different drugs that destroy the cancer cells. However, these very potent drugs can also cause damage to the patient’s healthy cells. These effects are short-term and long-term, because they cause harm to the growing bodies of the young patients.

Long-term effects of the treatment can be heart damage, second cancers, lung damage, infertility, cognitive issues, hearing losses and much more. Two-thirds of those who survive must face at least one chronic health condition for the rest of their lives. So, our key goal in the CLCRF Laboratory is to find therapies that have none of these long-term effects.

Leukaemia is a cancer of the blood. The leukaemia cells multiply uncontrollably, such that they crowd out the healthy blood cells. Leukaemia is the most common cancer in children. In a world-wide research effort, we helped to develop treatment protocols for leukaemia patients. They are very successful – today more than 85% of patients survive.

Sadly, this is not the case for babies who are diagnosed with leukaemia. Less than 40% survive. Our Laboratory team has focused on these very young patients, to find out why they do not respond to the drugs as well as older children do. What is the difference?

We found that the ‘mistakes’ or mutations that turn a healthy blood cell into a baby’s leukaemia cells are different from those in older children.

We managed to grow leukaemia cells from babies in the Laboratory, which was only possible because Jette Ford from our team has the skills to keep the leukaemia cells alive, such that they multiply – and we have a cell line.

Without these unique cell lines, our research to find better therapies could not have happened. The cell lines are absolutely critical to make a change for our youngest leukaemia patients. We screened many drugs that have come to market, and we found some that can destroy the leukaemia cells from the babies. Not only that, we also found out that these drugs work very well in combination. Best of all, these new drug combinations have fewer side effects.

It’s a matter of life and death.

By giving to the CLCRF you can help to improve the survival rate of children with cancer and better their response to treatment.

I am proud to say that our CLCRF Laboratory has attracted worldwide attention with our research into infant cancer. In Perth, our Laboratory boasts cell lines for testing that have been used across the world so that we can develop the best drug combinations to treat childhood cancer.

The CLCRF Laboratory is not government funded. Only one per cent of government funding is given to children’s cancer research. That is why your help is vital in the search for better treatment for children with cancer.

We rely on you to continue the dream of improving the lives of children with cancer. You can do this by investing in the legacy of research that we started.

There are still many drug combinations that our laboratory aims to test to better the lives of children with cancer. This testing is vital so that we can see more children survive, but we cannot do this without your help. Your money goes towards increasing their chances of survival and enhancing their lives.

In order for the Laboratory to continue with this life-changing research, we need your help. So please dig deep and give generously to the CLCRF.

To demonstrate my belief in this key research that the CLCRF Laboratory is leading, I will continue to be a board member of the CLCRF.

You’ve been so generous in the past, we are very thankful. The wonderful team of researchers that I have lead for 34 years is working around the clock to find the answers to make children’s lives better. But time is running out, so make a donation now to the Children’s Leukaemia & Cancer Research Foundation (Inc.) to help these little ones who suffer so greatly.

Yours sincerely,

Professor Ursula Kees

Dr Stirnweiss Makes Inroads into Fighting Resistant Cancer

Last year Dr Anja Stirnweiss, Senior Researcher at the Telethon Kids Institute, received a Children’s Leukaemia & Cancer Research Foundation (Inc.) (CLCRF) Project Grant that enabled her to evaluate pathways associated with drug resistance in NUT midline carcinoma, a type of aggressive cancer.

Further to this experimental work being conducted and analysed, Dr Stirnweiss submitted a Small Grant Application to CLCRF for support with the costs to finalise and publish the findings of this project.

In NUT midline carcinoma, the patient’s genetic material is incorrectly repaired, which leads to the joining of two genes (called BRD4 and NUT) and creates a new hybrid gene that causes the cancer. A new class of cancer drugs called iBETs, designed to block the function of BRD4, are currently assessed worldwide in 21 clinical trials for patients with leukaemia, brain tumours, aggressive breast cancers and NUT midline carcinoma.

Dr Stirnweiss’ findings indicate that the therapeutic benefits of these drugs are limited through the acquisition of resistance. This has important clinical ramifications.

For the study, she and her team used a unique collection of cell lines, obtained from NUT midline carcinoma patients, to identify drug-induced changes in gene expression. Dr Stirnweiss then performed a correlation analysis to identify changes that are unique to iBET-resistant cells.

Network analysis, which assesses how those genes are functionally connected to each other, highlighted the oncogene FOS to be a central player of the gene network that is associated with drug resistance. Removal of this gene from the resistant cells showed that FOS is not a driver of resistance, but an ideal marker to predict whether the cancer cells will respond to iBET drug treatment. Ultimately, assessment of FOS could be used in the clinic to predict whether patients will benefit from iBET treatment.

It was agreed that the findings from this substantial body of work is highly relevant to patients with NUT midline carcinoma and other cancers with BRD4 involvement. Therefore, the findings should be made available to other researchers and clinicians. To publish these findings in the highly prestigious journal, Molecular Cancer Research, minor work needs to be done. When completed, Ms Mahalia McEvoy, an outstanding young researcher who conducted experiments essential to the proposed manuscript as part of her Honours studies, will assist Dr Stirnweiss with writing the manuscript.

The Foundation approved a budget of $14,276 to cover these publication costs. Dr Stirnweiss passionately believes that this research presents a unique opportunity to make a difference for patients suffering from NUT midline carcinoma.

Congratulations and thank you to Dr Stirnweiss for her outstanding scientific contribution to cancer research.

Cracking the Cancer Code for Kids

‘Excitement’ and ‘cancer’ are two words that shouldn’t really go together, until you add the word ‘hope’ to the sentence. Those are the words flowing out of the mouths of researchers from the Telethon Kids Institute in Perth as they edge closer to answering what causes pediatric cancer, thanks to funding by the Children’s Leukaemia & Cancer Research Foundation (Inc.).

Dr Mark Cruickshank, who leads the Cancer Genomics and Epigenetics team, said it has been a long road to reach the pointy end of years of research and is excited to be on the verge of cracking the cancer code for kids. “This is one project where we have no idea what causes leukaemia in infants and that’s a really big focus of mine at present, because I’m very close to finding what we think are the answers to that conundrum,” Dr Cruickshank said. “It has taken more than four years to reach this stage, by studying the gene sequencing mutations in cells. This in turn has now escalated the drug therapy studies that are built on that gene research.”

Dr Cruickshank revealed that the research team has been analysing data from cancer cells of infants to identify mutations that are not present in patients’ healthy cells. As infants are ‘brand new’ to life they have had little time for their cells to mutate outside the womb, so there is something genetic causing them to have cancer. “We’ve found some extremely exciting signals from the data, statistical signals, and now we need to test these out in the laboratory. This could be a huge advancement and it could open up a lot of different avenues, for example we could look at cohorts of patients to see if a mutation is associated with treatment outcomes,” he said.

The genetic research and understanding has been crucial to take the team to this next stage as the make-up of the leukaemia affects whether the treatments will work or not. Having a genetic understanding can cut out the guessing games so patients can receive doses of drugs that are effective and also minimise the side effects to their bodies. “We already know some drugs fail in some patients and we think this is due to the genetics,” Dr Cruickshank said.

While researchers may have found the causes of the diseases, the next step is to develop the best treatment protocols to deliver to patients and their families.

“I don’t really think that gaining short amounts of extensions of life is where we need to end up, we really need to cure these diseases. I want to reach a point where the therapies aren’t putting the families through a year’s worth of pain and then a lifetime of uncertainty,” he said.

“I believe in finding absolute cures – and that is the goal of the research, to do that we need help. To accelerate the research we need to be able to test the drugs in all different ways and we need the best technologies. We have the capacity to do this, but it takes money to do it.”

If you would like to contribute support to Dr Cruickshank and his team’s research to help make a difference you can donate to CLCRF or contact the Foundation via email or phone +61 8 9363 7400 for further information.

Read a recent paper on infant leukaemia cell lines and drug screening published in Volume 31 of Leukemia Journal by Dr Mark Cruickshank

CLCRF funding to Dr A. Beesley

A landmark study that lifts the lid on key features of one of the most hostile cancers will soon be published with funding from the CLCRF.

One of the Foundation’s Fellowship recipients, Dr Alex Beesley with Dr Anja Stirnweiss have comprehensively described, for the first time, the genetics behind NUT Carcinoma.

NUT Carcinoma is one of the most aggressive human cancers, and there is a desperate need for effective therapies for patients with this illness. It is a rare genetically defined disease not specific to any tissue type or organ and common sites include the head and neck.

So far the cancer has been very resistant to standard chemotherapy treatments. Specialists have found that tumours may initially respond to therapy, but then rapid recurrence is experienced. Treatment must be tailored to the individual patient.

The study is a culmination of the research program that the Foundation has funded over the last several years, both in the form of project grants and Dr Beesley’s CLCRF Fellowship. This latest award of $12,000 will assist in the publication of the highly important document.

It is hoped that the manuscript will be submitted to the journal Oncotarget and it represents a milestone publication that will help inform therapy choices for this aggressive cancer.