Exciting research is laying the groundwork to develop a promising new targeted therapy for aggressive subtypes of childhood leukaemia including infant acute lymphoblastic leukaemia (ALL).

Lead investigator, Dr Michelle Henderson is a senior scientist, project leader and joint Research Manager of Molecular Diagnostics at Sydney’s Children’s Cancer Institute.

Before moving to the Children’s Cancer Institute, Dr Henderson spent 10 years working on the genetics and molecular biology of breast cancers at the Garvan Institute of Medical Research.

“Fourteen years ago, the opportunity to move to the Children’s Cancer Institute came up,” explained Dr Henderson.

“After spending years studying individual genes involved in cancer, I wanted to take a step closer to the clinic where I could potentially discover new treatments and have a more direct impact on people with cancer.”

While major research advancements have significantly improved survival rates in childhood leukaemia, Dr Henderson and her team are working to target certain subtypes of childhood leukaemia that still have very poor prognoses.

These include children who fail induction treatment, relapse during treatment or whose leukaemia harbours chromosomal rearrangement of the Mixed Lineage Leukaemia (MLL) gene*, an abnormality that occurs in 90% of infant ALL, with a survival rate of less than 50%.

“It can be an extra challenge with children as their bodies are still developing and these chemotherapeutic agents that work so well for leukaemia can still be very harmful to the patient,” said Dr Henderson.

“If it’s a more aggressive cancer then that child will receive more aggressive treatment and that can affect them later in life, leading to physical problems such as heart disease, osteoporosis, infertility, obesity, or even the risk of a second cancer.

“This presents an urgent need for the development of novel treatment strategies incorporating more selective, targeted therapies, allowing for a reduction in chemotherapy dosage and toxicity.”

For the past 10 years, Dr Henderson’s lab has collaborated with a lab in Buffalo, New York, conducting ‘screens’ with the aim of finding new drugs which specifically kill cancer cells without affecting normal cells.

Together they have discovered a new drug, OT-82, which has ‘remarkable’ potential to improve treatment in aggressive childhood leukaemia.

Dr Henderson’s research was awarded a Priority-driven Collaborative Cancer Research Scheme (PdCCRS) grant in 2019 to further develop this therapy.

This grant was co-funded by the Leukaemia Foundation, The Kid’s Cancer Project and Cancer Australia.

“This drug, OT-82, blocks the production of a cellular biochemical called nicotinamide adenine dinucleotide (NAD) which rapidly dividing cancer cells can be dependent on for energy,” said Dr Henderson.

“NAD is also a co-factor for a number of enzymes that help the cell repair itself and so leukaemia cells can require a lot of it because they’re continually growing and need to repair themselves all the time.

“Based on the knowledge that cancer cells depend on NAD more than normal cells, researchers have tried for many years to design a compound that actively targets and inhibits production of NAD. But a suitable compound was yet to be found.”

Although not looking to target this pathway in particular, Dr Henderson and her collaborators in the U.S. came upon such a compound through a screening strategy aimed directly at blood cancer cells.

“We were surprised when the compound that came out of the search appeared to be an inhibitor of an enzyme called NAMPT (nicotinamide phosphoribosyltransferase), which is necessary for producing NAD in the cell but whose association with blood cancers was unknown,” she explained.

“This particular compound universally kills blood cancer cells, but the normal blood cells just go into a pause.

“The normal blood cells don’t die, they are just in pause and then when you stop treating them, they rejuvenate again, whereas the cancer cells don’t.

“It’s interesting that we’ve come across it through a completely blind approach of just screening thousands and thousands of compounds and found one that targets blood cancer cells.

“This compound seems to be very well tolerated so far in adult trials and is earmarked for going further into paediatric trials.”

With this grant, Dr Henderson and her team are laying the groundwork for these paediatric trials, by determining which children could be most responsive.

“Part of our research is to determine exactly which subtypes of leukemia will respond, both on a broad, phenotype level, and at a molecular level, to find which genes are expressed in that particular cancer,” said Dr Henderson.

“We want to have a set of biomarkers, or subtype markers, that say if a patient has this cancer and it expresses this gene or mutation, they are more likely to respond to OT-82.

“So far, we have found a set of very responsive patient samples that each have mutations in DNA repair genes.

“We think that when they have a weakness in their DNA repair, with the cancer cell having to grow so rapidly and requiring NAD for repair, that’s when they are particularly responsive to OT-82.

“We are also looking at how OT-82 can be used in combination therapy to promote the response to other drugs currently being used for leukaemia treatment.”

The impact of this project is further enhanced by a collaborative grant recently awarded to the Children’s Cancer Institute to deliver personalised medicine to every child in Australia.

“It’s going to become a reality that across the country every child’s cancer will be sequenced,” said Dr Henderson.

“Such a completely individualised approach to treatment means that OT-82 could have an incredible impact on patient survival outcomes.”

Inhibiting NAD also appears to be relevant to some other cancers that depend on the same pathway.

“They might be solid tumours like sarcoma or brain tumours with certain genetic mutations you can screen for that cause dependence on this particular pathway,” said Dr Henderson.

The next big challenge for the research team will be gearing up for a paediatric leukaemia clinical trial.

“That’s why this funding from the Leukemia Foundation, The Kid’s Cancer Project and Cancer Australia is so important,” said Dr Henderson.

“Even though a relatively small number of children may have these high-risk leukaemia subtypes, it will have a significant impact on survival outcomes for this group and may be applied across other cancer types.

“The whole team is so thankful to have the opportunity to gather this supporting evidence and make a real case for OT-82 to be taken to clinical trial stage for these deadly childhood leukaemias.”

*Also referred to as Mixed Lineage Leukaemia Gene Rearrangement (MLL-r). This occurs when a piece of DNA is swapped with another chromosome which results in two different genes being abnormally joined together. The resulting protein can no longer control the development of the blood system and blood cells grow out of control, resulting in leukaemia.

The Leukaemia Foundation’s National Research program has supported the careers of the brightest researchers and clinicians, like Matthew Witkowski, for almost 20 years.

His research is a prime example of how critical research funding is to understand the biology and genetics of blood cancers and to developing new treatments.

Matt’s career trajectory was kick-started when he won the under 11s footy grand final for Diamond Creek in Victoria! He has since moved from sport to science and, after completing his Honours at the Walter and Eliza Hall Institute (WEHI) in Melbourne, was awarded a PhD scholarship from the Leukaemia Foundation.

Now he’s working as a postdoc scientist at the New York University School of Medicine in the U.S. and his sights are focused on improving the effectiveness of CAR T-cell therapy.

When ALL News spoke to Matt, he had just presented on The relapsed B-cell acute lymphoblastic leukaemia immune microenvironment and won the first prize post-doctoral Eugene Cronkite 2019 New Investigator Award at the International Society for Experimental Haematology conference in Australia.

He explained that back in 2011, when he applied for a PhD scholarship, “the Leukaemia Foundation was very competitive, but I was lucky enough to receive it”.

Matt’s PhD, from January 2012 to December 2014, was valued at $120,000.

“It was my first scholarship. It was a big deal for me, and relieved a lot of the stress,” said Matt.

“You knew someone cared about what you were doing as a student and that it was worth investing in. That’s critical at the point when you are learning the lay of the land in science.”

Matt did his PhD in lab of Dr Ross Dickins which was then at WEHI*.

“The Leukaemia Foundation was a big supporter of our lab and was a constant support and funding stream. Our lab thrived on that bit of stability,” said Matt.

“You do a lot of work all the time, in science. You’re constantly working, so you don’t want to worry about funding, especially when the Australian government can swing around in terms of how much they are investing in science.

“We were a small lab with one post doc, two students, and Ross as well. It was one of the few acute lymphoblastic leukaemia labs at WEHI at that time,” explained Matt.

“We were working on ALL because it is the most common cancer in kids and the most common cause of cancer-related death in children. I work on B-cell leukaemia, which is the most prevalent form of ALL.

“Students are the powerhouse of a lot of labs, especially ours.

“The other student in the lab, Grace Liu [also a Leukaemia Foundation three-year PhD scholarship recipient (2010-2012)] and I were producing a lot of the data.

“We both got meaningful papers out of it, which put us in good stead for building a career in the field” said Matt, and this was important for his career going forward.

Matt was investigating genes defective in leukaemia patients who showed resistance to chemotherapy, which would suggest that these particular genes dictated a patient’s ability to respond to chemotherapy.

“My work has focused on the Ikaros gene and defining how Ikaros interacts with other genes in a leukaemia cell to drive chemotherapy resistance and cancer development,” he said.

“By understanding these interactions, explanations for why patients who lack the Ikaros gene do not respond to therapy may become clear.

“Ultimately, this may lead to alternative therapy for ALL patients who would otherwise not respond to common chemotherapeutics.”

Matt had papers published in both Leukemia and The Journal of Experimental Medicine, and prior to completing his PhD, he went to a conference in Colorado in the U.S. where he met his current boss, Iannis Aifantis, an internationally recognised immunologist and cancer biologist, who heads a laboratory at New York University (NYU).

“He had read our papers and said, ‘do you want to come to New York for an interview in the lab?’.

“To be honest, New York wasn’t on my list. It seemed a little daunting. However, Luisa Cimmino, a previous postdoc with Ross Dickins, who was in the Aifantis lab, said ‘come to New York, it is really nice here’.

And so Matt went to further his career and research in New York. He went from a lab of four people to being a postdoc in a lab of 29! He’s still there now, continuing his work in ALL, “and it has been great ever since, just working away”, he says.

“I was able to extend on what I did in Ross’ lab. I worked in the same disease, ALL, but new technologies were coming out from the States and I could use them straight away.

“Leukaemia is a very complicated disease. You have a cell that is abnormal and it grows and grows in your bone marrow and spreads.

“What we did in Ross’ lab during my PhD, was provide really valuable information about what the genetic changes were in cells that made them transform into leukaemia. We used very novel tools to do that.

“Ross had brought that back from America and we took advantage of that to understand what underpinned leukaemia emerging and causing disease, and treatment resistance.

“When I went to America, I thought; how does the bone marrow itself influence the leukaemia? It obviously doesn’t grow on its own. It grows by interacting with everything around it.

‘When a patient presents with the disease that is throughout their bone marrow, then they get treatment, a small amount of leukaemic cells will just hang around and eventually the patient may relapse with the disease.

“My question was, ‘is there something that actually drives that small population of cells that are resistant to therapy to hang around, and what is the influence of the environment on these cells that would mean they would eventually not respond to therapy and inevitably cause relapse in these patients’.

“I was able to do a lot of that in the U.S. where we had new technologies where we could look not only at the leukaemic cell, but also everything surrounding it.

“We could deconstruct and pull apart the whole landscape of the bone marrow and understand all of the components and how they were talking to the leukaemia to keep it alive.

“What we have been able to do at NYU is use novel technologies to understand the whole system and how it evolves over time. We think we might be able to intervene with how the environment keeps the leukaemia alive, as a means of improving therapy,” said Matt, first author on a paper about this work that was published in Cancer Cell in June 2020.

“If you just stop these populations of cells from supporting leukaemic cells, you might be able to improve therapies that are already quite good in leukaemia.

“By just taking into consideration that you don’t just treat the leukaemia, sometimes you have to treat the things around it that would potentially support it surviving. This is a new paradigm in a lot of therapies.”

Matt has continued to keep in touch with an Australian ALL patient, India Papas, who he met through the Leukaemia Foundation when she was young.

“Every so often I ask Jodie [her mum] how India is going, and she seems to be doing really well…she has grown up.”

Matt said, looking to the future, his holy grail was to understand why some patients fail CAR T-cell therapy.

“This therapy harnesses a patient’s own immune cells to kill their tumour. It was originally utilised at the Children’s Hospital of Philadelphia and St. Jude Children’s Research Hospital (Memphis) as a way to treat B-cell leukaemia.

“Initially, it looked great. It looked like taking T-cells out of a patient and repurposing their own cells to kill tumour cells was going to be a really nice curative treatment.

“But it turns out that now we are a few years out from those initial trials, they [CAR T-cells] are not as effective as we thought. There are patients relapsing.

“It is an expensive therapy as well. In the U.S., it costs USD500,000 for a single treatment with this drug.

“There have to be ways to mitigate the relapsing that emerges from this. Not all of them are because of the drugs or because the B-cells they are targeting are naturally resistant. Sometimes there are other mechanisms.

“My goal is to start a group that tries to understand why patients fail this therapy.

“My initial work, in understanding how the bone marrow is composed, provides a good platform to understand how the environment informs how these new immune therapies are working.

“That is the goal in my immediate future, to start my own group where I can do this… to be around these therapies and take advantage of the fact that patients get biopsies which lets us see how they perform over time and why they don’t respond or why they do.

“There is also something called Bi-specific T-cell engagers. They hook leukaemic cells up to cells in the body that, if activated, kill leukaemia cells.

“There is a drug, called blinatumomab, that has done pretty well in this kind of field, where you are depending on the environment to kill the cells by using CAR T-cells and blinatumomab.

“Once we understand what the environment is and how it influences the leukaemia cells, it might inform us which patients may not respond to these drugs. We have made the assumption that the environment is going to allow these drugs to work, but we don’t know that,” said Matt.

Matt said he was open to potentially moving back to Australia to start his own lab or to do that somewhere in America.

“I may come back to Australia but I’m not definitive about anything at the moment,” he said.

* Dr Ross Dickins subsequently moved to the Australian Centre for Blood Diseases at Monash University.

** Mark McKenzie was supported by a three-year Leukaemia Foundation Postdoctoral Fellowship (2010-2012).