Are you curious about the future of cancer treatment? Learn from the researchers at the forefront.
Are you curious about the latest developments in cancer research? Are you curious about how new cancer treatments and approaches are changing patient outcomes? Watch now to learn more about the Auckland researchers who are investigating opportunities and possibilities in personalised cancer treatments.
Professor Peter Browett is curious, too. He is using next generation sequencing and more to understand more about the best treatments for patients to achieve better outcomes and minimize side effect. He is joined by A/Prof Nuala Helsby who is curious about the implications of inherited and environmental factors on the treatment of diseases. They are working on solving the puzzles associated with the future of cancer therapies.
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Video transcript follows.
Presentation by Prof Peter Browett, director for the Centre for Cancer Research at the University of Auckland and clinical haematologist at Auckland Hospital
“Personalised haematology – Giving the right treatment to the right patient at the right time"
My name is Peter Browett. I'm a director for the Centre for Cancer Research at the University of Auckland. I'm also a clinical haematologist at Auckland Hospital, and my research interests are around the genetics of leukaemia. Today, I have an opportunity to talk to you about our research on personalised haematology. Our goal is to improve outcomes for patients with leukaemia by giving the right treatment to the right patient at the right time.
If we look at the whole area of cancer, one of the biggest advances over the last decade has been the understanding of the genetics of cancer and looking at the changes that occur in the genome of cancer cells. This has allowed us to help with the classification of cancers and also identify potential targets for therapies. The goal of our research is to assess the impact of genomic testing on the management of patients with blood cancer. This is the clinical problem that we're dealing with.
I look after patients with acute leukaemia. On the left-hand panel, you can see a blood sample from a patient with leukaemia. These are the leukemic cells that proliferate in the bone marrow, take over the normal bone marrow, and spill over into the peripheral blood. On the right-hand panel, you can see two tubes of blood. The left-hand one is what our blood would look like if we took a blood sample and let it sit on the bench. The red blood cells would fall to the bottom, the plasma would sit on top, and across here, you can see a hazy layer. That's the white blood cells. Here is a blood sample from a patient with leukaemia. Here are the red blood cells, a lot fewer of them. Here's the plasma, and this layer here consists of all the leukaemia cells. In fact, when you look back into the historical medical literature, you'll find that leukaemia got its name from "leukos," meaning white, because of these leukemic cells in the blood.
As I mentioned, leukaemia is a cancer of the bone marrow and blood. It starts off in the bone marrow. On the left is a normal bone marrow, what yours or my bone marrow would look like. Here's a part of the bone, and this is the bone marrow with fat cells and developing blood cells. On the right is a bone marrow sample taken from a patient with leukaemia. You can see in pink the little bone fragments, but here, it's just replaced. All the normal developing blood cells are replaced by this infiltration of leukaemia cells. Consequently, the patients we look after, when they present, have signs and symptoms due to the failure of the bone marrow.
Patients are anaemic, with a low haemoglobin, resulting in less oxygen being carried around the body. Presentation includes tiredness, fatigue, and shortness of breath on minor exertion. There's also a failure of production of the normal white blood cells, our infection-fighting cells, known as neutrophils. Patients present with infections. Here's an example, a chest X-ray of a patient with pneumonia, where you can see additional white material in the upper lobe of the left lung. On the left-hand panel, you can see a patient with ongoing fever, a common presentation in patients with leukaemia.
And finally, patients may present with abnormal bruising and bleeding, and that's because the platelet count, which is the clotting cells, is low. Here you can see bruises and these little fine petechiae, often over the foot due to gravitational effects, and in the mouth on the mucosa, you can see bruising and bleeding. This is the issue that patients with acute leukaemia present with.
The problem we have when we're managing these patients in the field of personalized haematology is that, up until recently, we treated all patients the same way. The presentation is similar, clinical features are similar, and patients would usually be treated with curative intent, with the goal of putting the patient into remission and ultimately curing them. However, all patients received the same type of chemotherapy, resulting in variable outcomes. Not all patients went into remission, and some experienced subsequent relapses.
The goal of our research is to delve deeper and try to find out what the differences are between these patients with acute leukaemia and how we can individualize therapy for each patient. This approach can potentially improve their outcomes and reduce the side effects of therapy.
Our focus is on understanding the genetic changes that occur in leukaemia.
We started over two decades ago by looking at chromosome changes, which are part of the DNA of the cell that controls its functions and activities. Many blood cancers, particularly acute leukemias, have characteristic chromosomal abnormalities. For example, about half the patients we see with acute leukaemia have chromosome changes, which can help predict outcomes and sometimes alter our therapy approach.
However, not all patients have chromosomal changes, and this approach can only detect changes in the number and structure of chromosomes. It can't identify small mutations or changes within the genes themselves. This limitation led to the need for advancements in the field of molecular genetics.
We've compared the study of leukaemia genetics to an iceberg, where the chromosome changes represent what's visible above the waterline. But the majority of changes, or the bulk of the iceberg, is below the waterline in the field of molecular genetics. This involves looking at spelling mistakes and small mutations within the genes themselves, which has become possible due to advancements in science and technology.
Initially, we could only examine a small number of genes, but in the last decade, there have been significant technological advancements in gene sequencing. With modern technology and next generation sequencing platforms, we can now analyse the entire human genome in a 24-hour period. This has provided us with much more information about the genetic changes in leukaemia and other cancer cells.
Our study, the Auckland Myeloid Gene Panel study, aims not only to count the number of books in the library (representing genes) but also to examine each page for any missing pages and spelling mistakes that might occur within those books.
So, within the DNA and the controlling pathways for the leukaemia cells, we developed a panel initially with a 78 gene panel. These genes are involved in blood cancers, and we've now expanded that to 110 genes that we look at. The goals of our study were threefold: first, to identify specific mutations within the leukaemia cells that might change a protein we could then target with a specific therapy or drug; second, to find information that could guide treatment and alter the prognosis, indicating a more favourable or unfavourable outlook; and third, to investigate molecular biomarkers for monitoring the patient's response to treatment.
Here is an example of the type of report we generate from our myeloid gene panel study. It includes patient details, genetic and chromosome information, and identified mutations within the patient's leukaemia. Each patient undergoes this analysis, generating additional information alongside conventional data about the leukaemia’s appearance and chromosome studies.
One of our initial findings was that every patient's leukaemia was different at the genetic level, even if it appeared similar under the microscope. This diversity in genetic profiles highlighted the need for personalized treatment approaches.
Large international studies, in which we participated, demonstrated that in addition to chromosome changes, different molecular changes could predict outcomes for patients. These predictions were based on probabilities of remaining in remission, with some mutation profiles indicating better outcomes than others.
In our analysis of the first 100 patients in the myeloid gene panel study, we detected an average of just over three critical mutations per patient. These mutations play a vital role in the development of leukaemia. We also observed variations in the frequency of specific mutations, with some being more common than others.
Moreover, our research aimed to determine whether these genetic analyses influenced our treatment decisions and patient outcomes. We classified leukaemia into risk groups, such as good, intermediate, and unfavourable, using both conventional information and molecular classifications. The addition of molecular classification led to changes in risk group assignments for some patients, potentially impacting their treatment choices.
In approximately 50% of patients, we identified mutations that could potentially be targeted with drug therapy. These mutations altered proteins within leukaemia cells, making them "druggable" targets. For instance, we found that about 10% of our leukaemia patients had mutations in the IDH2 gene, which could be targeted with specific drugs, leading to improved blood counts and bone marrow appearances in some cases.
Furthermore, our research explored using mutations as biomarkers to monitor therapy and assess the depth of remission. We employed minimal residual disease monitoring, which allows us to detect leukaemia markers at a much lower level than conventional criteria. Lower minimal residual disease levels correlated with better outcomes, enabling us to refine treatment approaches.
Unexpectedly, our research revealed a higher incidence of familial predisposition to blood cancers than initially anticipated. While solid cancers typically have a 5% inherited genetic predisposition, we discovered that among the first 200 patients we studied, eight had an inherited predisposition. One example was the DDX41 gene, where an inherited mutation was identified in patients without a family history of leukaemia. These findings have implications for treatment recommendations, genetic counselling, and potential donor screening for stem cell transplants.
In summary, our research in personalized medicine for acute myeloid leukaemia goes beyond targeting specific mutations with novel treatments. It also enhances diagnosis and subtyping, predicts patient outcomes, identifies potential druggable targets, provides biomarkers for monitoring therapy, and uncovers familial predisposition to blood cancers. This comprehensive approach aims to improve the care and outcomes of leukaemia patients.
This work is in the blood cancer area, but I think the findings here also become applicable to other cancers. There's a lot of work going on both within the University of Auckland and the precision medicine field, and internationally looking at the impact of genomic testing and cancers. So thank you very much for tuning in. Thank you very much for your attention.
Can I just acknowledge I'm a very small part of all of this research? So this work was done in the Leukaemia and Blood Cancer Research Unit within the Centre for Cancer Research at the University of Auckland, led by Stefan Bohlander, my co-director of the LBCRU, and Purvi, who's the scientist who's driven through all our molecular work. We also work closely with our colleagues in molecular haematology at Auckland Hospital and our clinical colleagues at Auckland City Hospital who care for these patients. Finally, the patients and their families who consented to having their leukaemia DNA analysed as part of the study.
Presentation by A/Prof Nuala Helsby, Department of Molecular Medicine and Pithily, The University of Auckland
Hello, I'm Nuala Helsby, and I'd like to talk to you today about my research interest, which is cancer pharmacogenetics. As we've understood more and more about the cancer genome and the importance of the genome in both prevention of cancer and also our improved understanding of how to treat cancer, and by the genome, I simply mean the DNA molecules within the nucleus of cells. We've understood for a number of years now the role of the important role of environmental chemicals that can cause damage to the DNA, and they're called mutagens. If we can avoid those environmental DNA-damaging agents, we can help prevent and minimize the chances of getting cancer. So that's an important part of our understanding of the cancer genome.
Over the years, we've also understood that certain cancers can run in families, and these are called inherited cancer syndromes. Our ability to understand the genetic changes and the changes in the DNA in those individuals within families help us not only understand who's going to be at risk of developing some of these cancers but also developing screening programs to try to minimize or prevent the risk of people developing cancer.
Over the years, we've also improved our treatments of cancer by understanding more about how the cancer genome, the DNA inside cancer cells, works. One of the things that we do know is that cytotoxic chemotherapy drugs and radiation therapy damage the tumour cells by causing a lot of DNA damage inside those cells. But over the years, more recent years, we've also been able to start to understand that within one's cancer, a cancer type, there may be lots and lots of subtypes, and we call these molecular subtypes. They are because within each type of cancer, there might be lots and lots of different changes in the DNA, so somatic mutations in the DNA in those tumour cells. That might mean that some of those subtypes of cancers are overexpressing certain proteins and certain pathways, and that means we can then target those proteins or pathways with very selective new drugs that have more recently become available on the market.
I'm interested in something slightly different, though. I am interested in the person, not the tumour, not the cancer. I'm interested in something called cancer pharmacogenetics, and these are the inherited differences in how each individual person responds to therapy. In the context of cancer, I'm particularly interested in cancer chemotherapy. So I'm interested in pharmacogenetics, and that is simply trying to study and understand the inherited differences or differences in our genes between individuals that might mean that in some people, a drug doesn't work very well, and in other people, a drug might not be safe. So it's this real balance between the benefits and harms of a drug that might relate to your differences that you've inherited from your parents.
Now I work on both sides of this balance, but what I want to tell you about today is some work that we've been doing for many years now to try and understand why one particular cancer drug might not work in some people. So what I want to talk to you today about is this drug cyclophosphamide. Now it's one of the oldest chemotherapy drugs, and it's given as an intravenous drip to patients, and it's used. It's really key for the treatment of cancers such as breast cancer but also haematological malignancies which are blood cancer cycle lymphoma and leukaemia and also in some of the very rare childhood cancers.
Now, cyclophosphamide is this compound here. This is the chemical structure of cyclophosphamide, and it works by these two arms of the molecule attaching to DNA. And once it's attached to the DNA, it stops cells being able to divide, so that stops the cancer cells growing. So one of the other advantages of this ability of cyclophosphamide to bind or attach to DNA to prevent the ability of DNA to then copy itself to replicate, which is a key thing that's required for cells to grow and proliferate in your body. This ability to stop this process, stop DNA replication, means that cyclophosphamide is also very good at helping to treat certain autoimmune diseases. Those diseases are things like systemic lupus erythematosus and vasculitis. And that's because in autoimmune diseases, you've got a very activated immune system and lots of proliferating white blood cells that attack your normal tissues. So cyclophosphamide can dampen down and stop those proliferations of those very active cells.
But in the context of cancer, cyclophosphide has been increasingly used because of its immunosuppressive properties too. And in one context is where it's been used when patients have got haematological malignancies, some of those blood cancers. And one of the ways to treat that is to give patients a bone marrow transplantation. But if you don't dampen down your normal immune system with a little bit of a small dose of cyclophosphamide, then your normal immune system will start to attack that bone marrow transplantation. And that's called graft-versus-host disease, and it's one of the newer ways that cyclophosphamide is being used to help treat cancer patients with cancer. It's also being used in another very new approach to the treatment of cancer, and that approach is called CAR-T therapy, where T cells are taken out of your body. They are trained and adapted to help them identify your tumour cells as foreign. And then they're put back into your body to help target those and be able to attack and target your cancer cells. But to put these CAR-T cells, these altered T cells back into your body, you need to provide a little bit of space inside all of your immune system. And one way to do that is, again, to give a little bit of cyclophosphamide just before you give the reinfused these T cells back into the body. And that's called a preconditioning to give a niche or a tiny little space to help these T cells be able to repopulate into your body.
So why does this drug cyclophosphamide not work in some people? Cyclophosphamide is actually a very complicated drug. So cyclophosphamide itself isn't active. It's called a prodrug. It has to be converted. It has no activity. It has to be converted in our bodies, in our livers, into a molecule called 4-hydroxy-cyclophosphamide that
then converts and balances itself with a compound called aldo-phosphamide. And then there's one further step where aldo-phosphamide gets converted into a molecule called phosphoramide mustard. And it's this phosphoramide mustard that attaches itself or alkylates DNA, and that attaching and alkylating DNA is what stops the DNA being able to replicate. So it stops the cell growth.
But it also, in a cancer cell, will tell the cell to undergo cell death, to go onto a process called apoptosis. Using human liver, that some individuals are very good at activating cyclophosphamide into this 4-hydroxy-cyclophosphamide metabolite. So some of us are very high activators of cyclophosphamide. Other livers are very poor activators of cyclophosphamide. And again, some are somewhere in between, so intermediate activators of cyclophosphamide.
This activation of cyclophosphamide in the liver is undertaken by some enzymes, and the enzymes involved are called CYP2C19 and CYP2B6. Now, these enzymes, we've inherited differences in the activity of both of these enzymes, and the differences in the activity that we've inherited are simply due to something called single nucleotide polymorphisms or single nucleotide polymorphisms or Snips in the genes that code for each of those enzymes. So if you're not sure what a SNP is, it's basically the code for within each gene that encodes for a protein has a series of letters within it. And if one of those letters gets changed, for example, a change from a G to an A, then that is a single nucleotide polymorphism. And if you have one of these very small letter changes in the gene for either CYP2C19 or CYP2B6, then the activity of that enzyme is very low or non-existent. And because we have inherited two copies of the gene from our parents, one from our mother and one from our father, then the children of the parents can have either inherited two normal copies, in which case CYP2C19 and CYP2B6 enzyme would say that they've got normal activity of those enzymes that can activate cyclophosphamide. Or they might have inherited two changed copies of the gene from their parents, and that means that then they've got very poor activity for either CYP2C19 or CYP2B6, and their ability to activate cyclophosphamide in their liver.
Some individuals will have inherited one normal copy and one changed copy of their genes, and they will have intermediate activity for activating cyclophosphamide by their liver. Unfortunately, the pattern of these letter changes, these SNP changes in genes, is actually quite complicated. But all you really need to remember is that for CYP2C19, there are two common SNP changes that occur. And if you inherit any pattern of these SNP variants and you inherit two of these copies that are variant genes with low activity, then you will be a poor metabolizer of drugs such as cyclophosphamide because you've got no enzyme and therefore no activity. And that's sometimes called null.
For CYP2B6, though, it's a bit more complicated because it's a very complex gene. But all you really need to remember for in the context of today is that if you've inherited a pattern of two variant SNP changes in your gene, which is called the star 6 variant, then you will have low enzyme activity. And if you've inherited essentially two copies of this star 6, which has two SNPs in it, then you are also likely to be a poor metabolizer of cyclophosphamide with very low activity of being able to activate the drug.
A number of years ago now, we were able to demonstrate using human liver material that individuals who had inherited at least one variant copy of their gene in either CYP2C19 or CYP2B6 were poor metabolizers of cyclophosphamide and had much lower activation of cyclophosphamide in their liver. So we've been able to show that if you've inherited a low-function enzyme for either CYP2C19 or CYP2B6, that certainly, within liver samples, you can see decreased activation of cyclophosphamide into 4-hydroxycy-clophosphamide. But that's only the first step in the activation of this drug to form that agent called phosphoramide mustard that interacts with DNA and causes all the stopping cells, like cancer cells, from proliferating and growing.
So do these inherited differences in activation matter? Do they have a clinical outcome? We decided to look at that in two different ways. And the first way we was we decided to look to see what was already known in the literature. So we had an extensive look through all the material that had been published in the literature. And we found that when we looked at the data, there were a number of studies, 13 studies, which had shown that in patients, you could see differences in how much of that activated four-hydroxy-cyclophosphamide was formed and circulating in their blood supply ready to interact with tumour cells and kill tumour cells. But what we also found was that there were 17 studies which
had shown that if you've inherited any of those SNPs in either CYP2B6 or CYP2C19, then patients will have worse outcomes when they're treated with cyclophosphamide. So they'll have worse survival following treatment with cyclophosphamide, whether it is breast cancer treatment, leukaemia, lymphoma treatment, or another blood cancer called multiple myeloma. And even worse treatment outcomes in that. And one of those autoimmune diseases that cyclophosphamide is sometimes used for, a disease called lupus, there was very variable quality of the data. So some studies had only looked for changes in inherited differences in CYP2B6, and other studies had only assessed CYP2C19. So there is still a little bit of uncertainty in the literature as to the importance of the inherited differences in both of these genes.
So we then wondered if there is this strong signal from the overseas literature, can we see the effect of these inherited differences in CYP2C19 and CYP2B6 in New Zealand patients? So we decided to look to see if we could see these inherited differences in how patients can activate cyclophosphamide in patients who were being treated with cyclophosphamide for breast cancer. And what we did was we took blood samples from the patients while they were receiving their cyclophosphamide and measured to see if we could detect the formation of that four-hydroxy-cyclophosphamide metabolite in relation, and not to see the differences in the levels of that metabolite in comparison to their inherited differences in those two genes, CYP2C19 and CYP2B6.
And that's exactly what we saw. When we measured the concentrations of four-hydroxy-cyclophosphamide in their blood samples, we could see that if you've inherited a low-function of CYP2C19, you had lower metabolism, lower formation of that metabolite, lower activation of cyclophosphamide. And the same was also true of inheriting increased inherited variant copies of the CYP2B6 gene. Too many copies of variant copies, and you have lower bioactivation of cyclophosphamide. It is well established across different geographical regions of the world there are different prevalences of genetic variants. And it's fairly well understood that people from parts of Asia and Southeast Asia tend to have a higher prevalence of variants in the CYP2C19 and CYP2B6 genes. And that means people from those regions of the world are more likely to be poor metabolizers of drugs like cyclophosphamide than people of European ancestry. Now, we don't know very much at all about the prevalence of these gene variants in people of Māori and Pacific ancestry. But in our study, what we did note was that people who self-identified as not Pakeha had much lower activation of cyclophosphamide than individuals who identified as Pakeha New Zealanders.
Unfortunately, it's a little bit more complicated, and that's because there are some other factors affecting the enzyme activity of those cytochrome P450 or CYP enzymes that are involved in the activation of cyclophosphamide. And that's because there's increasing awareness that other factors, environmental factors, can interact with your genes to decrease the activity of these enzymes. And one of those environmental factors is the body's inflammatory response to the presence of a tumour in your body. And in this case, you might have inherited normal copies of the gene, so you should be a normal metabolizer. But the environmental effect of all this inflammation that occurs in your body is it switches it down-regulates or essentially switches off how well that gene is processed. And so you become a poor metabolizer. And this difference between your genes saying you're a normal metabolizer and your body's actual process, where you're a poor metabolizer, is called a phenocopy. And so, importantly, your genotype will not predict your phenotype when you have a large inflammatory response. And these individuals are sometimes called discordant from their genotype.
Now, CYP2C19, which is one of those enzymes that's important in the activation of cyclophosphamide, is particularly vulnerable to this down-regulation or changing the activity of the gene for CYP2C19. And we've been able to show over a number of different studies over the years that there are a substantial number of cancer patients who are discordant for CYP2C19. So they've got normal CYP2C19 genes, but they've got poor metabolism of the enzyme with this enzyme. And we can do that by probing the activity of this enzyme with prodrugs for CYP2C19. And we've done that over a number of different studies, and typically it's about 25% of patients at any one time have very low CYP2C19 activity that has nothing to do with their genotype. So it is a little bit more complicated than just simply your inheritance.
CYP2B6, in contrast, just doesn't seem to have the same gene-environment effect. And that means that after a patient has had multiple cycles of chemotherapy treatment with cyclophosphamide, the CYP2C19 gene no longer predicts whether they're going to be a poor activator of cyclophosphamide or not. However, the inherited differences in the CYP2B6 gene still strongly predict which women are going to have low activation of cyclophosphamide.
So I hope I've been able to explain to and persuade you that that first initial step of converting the inactive cyclophosphamide into an active compound by the human liver does involve these two enzymes, and is particularly inherited differences in CYP2B6 are probably very important in patient outcomes. But what's this four-hydroxy-cyclophosphamide metabolite has been formed, it readily forms another compound called aldo-phosphamide. And this compound is complicated because this metabolite can then be detoxified, it can be removed from the body by an enzyme called aldehyde dehydrogenase. And this enzyme also has a lot of inherited differences in its activity. And this is just not well-studied in any population anywhere in the world, and is something we still need to understand more about. And it's important because we do know that tissues that have high levels of this enzyme aldehyde dehydrogenase are protected from the toxic effects of cyclophosphamide. And that's how some of the bone marrow stem cells are protected from very high concentrations of very high doses of cyclophosphamide.
But once aldo-phosphamide has been formed, the way that it can convert into phosphoramide mustard, interact with the DNA, stop DNA being able to copy itself, replicate, and let cells, cancer cells in particular, proliferate and grow has always been assumed that this step is a simple chemical conversion, and that it doesn't involve any enzymes. However, we've very recently been able to show that we think that this final step is actually an enzyme-catalysed step. So, as I said, it's always been assumed that this conversion of aldo-phosphamide into this final reactive compound that interacts with DNA, binds to DNA, in a process that's called alkylation, that this process has always been assumed to be a simple chemical reaction. Simple conversion. And we think that we've been able to show now that it's actually an enzyme-catalysed reaction.
And we think that this enzyme is not actually an enzyme. We think it's actually an enzyme-protein. So it's a protein-protein complex that's involved in this final step. And we also think that the enzyme-protein complex is not just a simple enzyme. It's what we call a multiprotein complex. And a multiprotein complex is where you've got a number of different enzymes and proteins that all work together to help catalyse a reaction. And so we've done some experiments with purified human proteins that are involved in the activation of cyclophosphamide. And we've also been able to show that, in particular, when we look at a protein that's important in forming the aldo-phosphamide, so it's important in that step just before the last step, we've been able to show that if we remove that protein from a human liver cell, then you lose the ability of that liver cell to form the final activated compound that interacts with DNA and causes DNA alkylation and binding of that to DNA. So that's a critical step for killing tumour cells. We've also been able to show in that same study that, importantly, if we remove that particular protein from a normal human liver cell, then that cell also loses its ability to alkylate DNA.
So what this means is that this enzyme, and this protein-protein complex that we've shown is involved in this final step, it suggests that they are key to forming the DNA alkylating agent that causes cancer cells to undergo cell death. And so we think that they might be a key therapeutic target that might allow us to improve the ability of cyclophosphamide to treat cancer cells and to kill tumour cells. So in conclusion, cyclophosphamide is actually quite a complicated drug, and its activation by the liver involves a number of different enzymes. And we've been able to show that there are quite large inherited differences in the activity of these different enzymes, in particular, CYP2C19 and CYP2B6, that seem to be able to influence the outcome of treatment with cyclophosphamide. And we've also been able to show that there are some environmental factors, such as the inflammatory response in the body, that can also interact with the activity of these enzymes.
But it's also a reminder that we still don't fully understand all of the factors that influence the activation of this particular drug in patients, and it's something that we're continuing to work on. And finally, the initial process of forming an active DNA alkylating agent that allows us to kill tumour cells does involve enzymes and protein-protein complexes. And this complex may also be a therapeutic target to try and improve the effectiveness of cyclophosphamide for treatment of cancer.
Thank you very much for your attention. Can I just acknowledge, I'm a very small part of all of this research. So this work was done in the Leukaemia and Blood Cancer Research Unit within the Centre for Cancer Research at the University of Auckland, led by Stefan Bohlander, my co-director of the LBCRU, and Purvi, who's the scientist who's driven through all our molecular work. We also work closely with our colleagues in molecular haematology at Auckland Hospital and our clinical colleagues at Auckland City Hospital who care for these patients. Finally, the patients and their families who consented to having their leukaemia DNA analysed as part of the study. Thank you very much for your attention, and I'm happy to take any questions.
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