Approved Projects 2024

Childhood Leukaemia Research: Discovering a New DNA Damage Process 

1) What is this research about? 

Our immune system constantly makes new antibodies to fight infections. To do this, it rearranges DNA inside our immune cells, a bit like shuffling cards. But sometimes, mistakes happen. We've discovered a brand-new way these mistakes can damage DNA and lead to a childhood blood cancer called Leukaemia. We call this process "cut -and-run."

2) Why is it important? 

Although treatments for childhood leukaemia are often succcessful, some children relapse, and these cases are much harder to treat. Our research shows that "cut-and-run" damage may be one of the main reasons leukaemia comes back. 

3) What are the researchers doing? 

We are studying leukaemia samples from children to see how often ""cut-and-run" causes the DNA changes that lead to relapse. We will compare samples from diagnosis and relapse to look for a clear link between this process and treatment resistance. 

4) How could this help patients in the future? 

If we confirm that "cut-and-run" is a big driver of relapse, we could develop medicines to block it - without harming the immune system's normal infection-fighting ability. This could help stop leukaemia from coming back and imrpove survival for more children. 

Published in Nature:   Excised DNA circles from V(D)J recombination promote relapsed leukaemia | Nature

Understanding the Role of Epigenetic Modifiers in Early T-Cell Leukaemia 

1) What is this research about? 

This project focuses on Early T-cell Precursor Acute Lymphoblastice Leukaemia (ETP-ALL), a rare and aggressive blood cancer that begins in immature T-cells. The research aims to understand how changes in molecules that control gene activity, called epigenetic modifiers, influence how this leukaemia starts, survives treatement, and comes back. Specifically, it looks at how mutations in genes like EZH2,  may drive leukaemia progression and resistance to therapy. 

2) Why is this important? 

ETP-ALL has one of the highest relapse rates of all T-cell leukaemias, with up to 74% of patients experiencing the cancer's return. Standard treatments often fail, especially in patients whose cancer cells resist chemotherapy. These resistant cells, called leukaemia-initiating cells (LICs), are thought to survive and re-grow the disease after treatment. By uncovering how specific epigenetic changes fiel the survival of these cells, researchers hope to find new ways to prevent relapse. 

3) What are the researchers doing? 

The team is studying how genetic mutations in epigenetic regulators like EZH2, affect leukaemia development and treatment resistance. They will use advanced single-cell techniques to examine the unique features of cancer cells in ETP-ALL, and test how drugs targeting these epigentic changes might improve reponses to therapy. They are also exploring how the cell's internal clock and immune signalling pathways interact with theses epigentic factors. 

4) How could this help patients in the future? 

If certain epigentic mutations are found to drive treatment resistance or relapse, they could serve as biomarkers to identify high-risk patients early. More importantly, this research could lead to targeted therapies that block these epigentic drivers, making leukaemia cells more sensitive to treatment. Ultimately, this could offer new hope for children and adults battling aggressive forms of T-cell leukaemia. 

Published in Blood: NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance - PubMed

 Investigating the consequences of CEBP dysregulation in acute lymphoblastic leukaemia. 

1) What is this research about? 

Our genetic code can be thought of as a recipe book: genes are the ingredients, and special switches (called enhances) are the instructions that guide when and how those ingredients are used. In a rare and aggressive form of blood cancer called B Cell Precursor - Acute Lymphoblastic Leukaemia (BCP-ALL), these switches sometimes move to the wrong place. This can turn on genes, such as members of the CEBP family, at the wrong time, disrupting normal blood cell development and helping cancer cells grow. This research is focused on understanding how these misplaced "instructions" drive the disease. 

2) Why is it important? 

While most children with BCP-ALL respond well to treatment, teenagers and young adults with this subtype often relapse and have poorer outcomes. Current therapies aren't tailored to the specific genetic changes driving their cancer. By studying how the CEBP genes are switched on and how they affect leukaemia cells, researchers hope to find new ways to indentify high-risk patients earlier and develop more effective, targeted treatments. 

3) What are the researchers doing? 

The team is bringing together patient samples and genetic data from international collaborators. They are mapping how CEBP genes interact with DNA, how they change gene activity, and what happens when these genes are blocked or removed in both laboratory experiments and specialised mouse models developed from patient samples. They are also testing existing drugs that might interrupt these faulty instructions and prevent cancer cells from thriving. 

4) How could this help patients in the future? 

This research could provide new markers to predict who is most at risk of relapse and help design more personalised treatments. By targeting the cancer's "recipe errors" directly, future therapies could be more effective and have fewer side effects, ultimately improving survival and quality of life for patients with this high-risk form of leukaemia. 

Understanding Infant Leukaemia in the Brain and Spinal Cord 

1) What is this research about? 

This project focuses on infant leukaemia, a rare and aggressive form of blood cancer that develops in babies under one year of age. Specifically, it looks at why this cancer often spreads to the central nervous system (CNS), which includes the brain and spinal cord, and how leukaemia cells survive there even druing treatment. 

2) Why is this important? 

More than half of babies diagnosed with this form of leukaemia do not survive, even with intensive treatment. When the cancer spreads to the CNS, it becomes even harder to treat and often returns after therapy. Understanding how leukaemia cells hide and survive in the CNS could help researchers predict which children are most at risk and design better treatments. 

3) What are the researchers doing? 

The researchers have found that a molecules called miR-93, which helps control cancer cell growth, may play a key role in helping leukaemia cells survive in the CNS. In lab models, reducing miR-93 made it harder for these cells to live in that environment. Now they are studying patient samples from both the bone marrow and the CNS to see if the same thing happens in real life. 
 

4) How could this help patients in the future? 

If miR-03 is confirmed to help leukaemia cells survive in the CNS, it could be used in two ways: as a biomarker to identify patients at high risk of CNS relapse, and as a treatment target to stop cancer from coming back. This could lead to more effective, personalised therapies for babies facing this devastating disease. 

Overcoming tumour extracellular matrix barriers to effective CAR-T cell therapy for neuroblastoma.

1) What is this research about? 

This research focuses on improving a promising cancer treatment called CAR-T cell therapy for neuroblastoma, a common and often aggressive childhood cancer. Specifically, it looks at how the structure suurounding tumour cells, the extracellular matrix (ECM), acts like a shield that stops CAR-T cells from reaching and killing the cancer. The project aims to understand this barrier better and find ways to help CAR-T cells get through it more effectively. 

2) Why is it important? 

Neuroblastoma can be very hard to treat, especially in high-risk cases where current treatments only cure about half of patients. While CAR-T therapy has shown promise in some cancers, it hasn't worked well yet for neuroblastoma because the tumour environment protects the cancer for immune attacks. Finding ways to overcome these protective barriers could lead to better longer-lasting treatments and improved survival for children with this disease. 

3) What are the researchers doing? 

The team is studying samples of neuroblastoma tumour tissue to identify which parts of the ECM block CAR-T cells from attacking cancer cells. They use a special lab model that mimics the tumour's complex environment but without living cells, allowing them to test CAR-T cells move and work. They will also engineer new CAR-T cells that carry enzymes to break down the tough ECM, helping these immune cells penetrate the tumour better and kill cancer more effectively. 

4) How could this help patients in the future? 

If successful, this research could lead to improved CAR-T cell therapies that overcome the tumour's natural defences. This means children with neuroblastoma might recieve treatments that not only attack cancer more powerfully but also work for longer periods, increasing the chance of cure and reducing the chance of relapse. Ultimately, it could make CAR-T therapy a more effective and widely available options for children facing this challenging cancer. 

ALLTogether team science – development of a preclinical testing platform to improve outcomes for drug resistant T-cell Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is the most common cancer in children and can affect either B - or T cells. When T-cell leukaemia does not respond well to initial treatment (called resistant disease) or reoccurs (relapses), only two or three out of ten children will be cured. 
Research into better treatments for T-ALL has been difficult because the number of patients in each country is small. To overcome this, 14 European countries have joined to develop a single clinical trial for children, teenagers and young adults called ALLTogether1. Because this trial is so large, we now have a golden opportunity to study patients with T-ALL. This will help us understand why some T-ALLs do not respond to chemotherapy and help us find new drugs for patients with relapsed T-ALL.  
We aim to study changes in genes and proteins in unresponsive T-ALL cells after expansion of these cells in immune-deficient mice. Excitingly, we will use artificial intelligence to create computer simulations of the composition of the leukaemia to predict response to novel treatments. 
In addition, we will start testing leukaemia cells in the lab to see how combinations of already existing drugs will kill these leukaemic cells. We expect that our research will speed up drug development and personalised treatments in the future. Moreover, we will share this valuable resource of patient samples, gene and protein analyses, and new drug treatments with doctors and scientists in Europe (and beyond) to improve cure rates for patients with T-ALL
 

Detecting lingering cancer before it grows back

We are conducting research into whether cerebrospinal fluid (CSF), which is in the ventricles in the brain, contains lables (which we call biological markers or biomarkers for short) of brain cancer. Focussing on ependymoma, we have been looking for metabolite biomarkers, which are used in cell metabolism and may be released into the CSF from tumour cells. 

Cell metabolism creates energy for the cell and builds components of the cell structure. Indeed we found some biomarkers of ependymoma in CSF samples taken from children by lumbar puncture, as the biomarker metabolites were found at a different level in ependymoma CSF compared to healthy CSF. These biomarkers were seen after sugery when most tumour was removed, and should therefore be markers of lingering cancer cells. Lingering cancer cells are normally treated by radiotherapy but the cancer grows back in half of the ependymoma patients. We wish to see if these nine biomarkers are found in CSF from relapsed ependymoma patients and then, across a time frame, how early on in treatment we can see these labels of relapse. If the biomarkers are found only in the patients who relapse, after the end of treatment and in their relapsed tumours, we could predict who will relapse and treat them further. In future we could find these biomarkers by monitoring patients during and following radiotherapy for 2 years. This could lead to diagnosing relapse earlier than by using MRI scans, which could facilitate earlier treatment and perhaps a better outcome for the child. This addresses one of the Top 10 Children’s Cancer Priority Setting Partnership Research Priorities (number 5), which is "Why do children relapse, how can it be prevented, and what are the best ways to identify relapse earlier?" The metabolite biomarkers that we found point towards metabolic pathways that are potential new therapeutic targets for patients who need further therapy to prevent relapse. Those most abundant in ependymoma included metabolites in the export of acetyl- CoA from the mitochondrion (2 metabolites), in aerobic glycolysis (2 metabolites), and some amino acids (5 metabolites), whilst a sugar acid and an amino acid derivative were decreased in abundance (2 metabolites).
Therefore we might also address Research Priority number 1, "Can we find effective ... treatments for cancer including relapsed cancer?". Our proven method, liquid chromatography coupled to mass spectrometry targeted at our biomarkers, can effectively separate out, detect and quantify our biomarkers. We expect to deliver a test based on quantities of some of these biomarkers which can accurately determine if a patient is relapsing early on after the treatment for their primary tumour has ended.

Development of paediatric in vitro and in vivo models to study genetic and non genetic determinants
of cancer and foster new drug development.

Cancer is the leading disease-related cause of death in children 1-15 years old. Most deaths are due to cancer which becomes resistant to conventional therapies. Understanding why cancer develops, what mechanisms lead to relapse, how it changes over time and how it interacts with the immune system is crucial to developing new drugs to fight cancer. In vitro and in vivo models allow to study cancer, and also test new drugs. Different research questions require different models to study and be tested. This project aims at equipping the scientists in the institutions involved with several models, so that they can use the best model for each question and also validate the results in different models. We are particularly interested in three areas: 1. Generate PDX, which are known to recapitulate in vivo the human disease, and allow expansion of the tissue for further studies; 2. In vitro drug testing: we will grow tumour cells in vitro and we will test a battery of drugs that could help the child, to see if this approach could help the clinicians choose the treatment; 3. We will grow organoids and study how the immune system interacts with cancer.

The tools developed through this project will become available to other scientists through collaborations, so that we can maximize the impact of this project.

Expanding our understanding of CML-like Ph+ALL – are all patients at increased risk of relapse?

Acute lymphoblastic leukaemia (ALL) is a type of blood cancer that affects children and adults. It is an aggressive disease that needs intensive treatment with chemotherapy. One reason people may get leukaemia is that abnormalities develop in their genes. One such example of this is called the Philadelphia chromosome (Ph+). This is a bad risk ALL and is often associated with poor responses to and relapse following treatment. Ph+ is also seen in another type of leukaemia, called chronic myeloid leukaemia (CML). This type of leukaemia behaves very differently to Ph+ALL because the genetic abnormality is in an immature stem cell. Stem cells are the manufacturing system in the bone marrow that can mature into any of the three major and mature blood cells (white blood cells, red blood cells or platelets). In Ph+ALL, the genetic abnormality is in a mature white blood cell, termed a lymphoblast. It has always been assumed that CML and Ph+ALL are different diseases. However, recent scientific research from our research lab and others have suggested that in some children there is an overlap, and these cases have been termed ‘CML-like Ph+ALL’. This is a new type of leukaemia and research is needed to understand the disease better. However, we already know that these patients may have poorer outcomes to routine treatment and that they may need to be treated more like CML. In this project, we will investigate CML-like Ph+ALL in children. 

Exploring clonal evolution in rare (biclonal) aneuploid B-ALL cases

In children's leukemia, specifically in a type called B-cell acute lymphoblastic leukemia (B-ALL), the number of chromosomes within the cancer cells can vary. This variation, known as aneuploidy, is a common characteristic of this disease. When these leukemia cells have more chromosomes than normal, ranging from 52 to 67, it's called hyperdiploidy and is usually a sign that the patient might have a better chance of recovery. On the other hand, having fewer chromosomes than normal, less than 46, which is referred to as hypodiploidy, often indicates a tougher battle ahead with a poorer outlook. Our research focuses on a rare form of B-ALL where patients have both types of these abnormal cells at the same time—both the "extra chromosome" cells and the "fewer chromosome" cells. This situation provides a unique window into how different cancerous cells compete or cooperate within the same body, which can teach us a lot about how the disease progresses, how it might resist treatment, and why it sometimes comes back after treatment. Understanding the mix of these cancer cells in detail requires a deep dive into their genetic makeup, which is what we aim to do. By identifying the specific genetic changes that drive the growth and evolution of these cancer cells, we can learn more about how to fight them. To study this, we use a mouse model that can host human leukemia cells, allowing us to observe how the disease evolves in a living organism. This method will give us important insights into the unique biology of these rare mixed cases, potentially leading to better ways to treat and manage children's leukemia in the future. In simpler terms, we are exploring the genetic landscape of a unique and rare form of children's leukemia to uncover new knowledge about the disease that could lead to improved treatments. By studying how different cancer cells interact in the body, we hope to find better ways to tackle leukemia and give patients a brighter future.

Functional Biomarker Discovery in Paediatric Cancer: A Pathway to Personalised Therapy

Many childhood cancers have good outcomes, but patients with tumours that progress or relapse, like those  with neuroblastoma (NB) and rhabdomyosarcoma (RMS), often face poor outcomes due to limited  effective treatments. Understanding the biology of treatment resistance is crucial to improve risk  predictions and treatment options. In the meantime, these children need more individualized treatment  approaches to increase their chances of a cure. 

Recent evidence shows that paediatric cancer cells can adapt and survive treatment by changing their  behaviour through a process called cellular plasticity, without altering their DNA. Our lab has  developed molecular methods to study plasticity in individual cells over time, leading to an unprecedented understanding of plasticity and how it is a key driver of treatment resistance and  relapse in childhood cancer.  

We think translating plasticity knowledge into the clinic will help predict which patients are at risk of relapse  and develop innovative treatment options. To this end, we will aim to identify plasticity biomarkers in  early diagnostic/biopsies and metastatic/relapsed samples of clinically annotated paediatric cancer  patient samples using high-resolution single-cell technologies that probe the non-genetic space (the  epigenome). This will identify plasticity in patient’s samples and provide proof-of-evidence of their  predictive capability which could be further explored in larger cohorts. 

Through this proof-of-feasibility/principle study, we hope to develop a new methodology to tailor  treatment to each individual patient that could be tested in subsequent clinical trials.  
 

Identifying more efficient therapeutic targets for paediatric AML using CITE-seq

Acute myeloid leukaemia (AML) is an aggressive cancer of the blood system and is the second most common type of paediatric leukaemia. Despite a five-year survival rate of around 44%, treatment options are scarce and overall survival has shown modest gains with the increase of treatment intensity. In addition, cancer cells can evade or don’t respond to treatment, accounting for disease relapse in over 50% of patients (1). Besides new AML treatments largely relying on adult patient studies that might not translate to paediatric AML, recent advances have been only achieved by intensifying standard chemotherapy, increasing treatment-related toxicity and off-target effects (2). Thus, demonstrating the need for new targeted therapies. Cancer research has focused on understanding how the genetic elements (those encoded in our DNA) are
regulated by internal and external factors, such as hereditary factors and tobacco, respectively (3). However, there is a large gap in our fundamental knowledge of the most "druggable" targets in cancer, the proteins - molecules carrying the majority of cellular functions. Our most recent studies on protein biology identified a specific target that kills cancer cells while protecting healthy cells in adult AML, specifically, we targeted leukaemic stem cells (LSCs), the entities responsible for disease initiation and relapse, while protecting healthy stem cells, and offering a new therapeutic target with potentially lower treatment burden (4). Thus, this study proposes to characterise the genetic messenger and protein landscape of paediatric AML using novel state-of-art technology (CITE-seq), with the aim of improving disease prognosis by unravelling LSC evasion mechanisms and identification of therapeutic targets with reduced toxicity. This work will develop new strategies to study development and evasion of blood cancers, provide a platform of annotated LSC populations to the paediatric AML research community and allow our group to apply for larger grants in order to continue studying new targets that could offer more effective therapies for paediatric AML.

Near Infra-red fluorescence in Wilms tumour organoids

The day of surgery for removal of the cancer is one of the most stressful for children and families. This innovative project aims to improve Wilms tumour (WT) surgery and make that surgery easier, better, and safer. During surgery, the surgeon cannot see all the areas of disease and cancer cells may be left behind. Extra tissue may be taken to ensure all the tumour has been removed, but this can be unnecessary. Our team of world experts in fluorescent chemistry, surgery, organoids and genomics research will develop a dye that makes tumour cells glow so that during the operation surgeons can see exactly where the tumour is. 
Initially we will take samples from WT removed at Birmingham Children's Hospital and grow these in the lab into a mini-tumour (organoid). Then Indocyanine Green (ICG) and triazole-N-cyanine (TNC) dyes will be tested to see which ones the tumour will take up. WT does not readily take up ICG, so at best it may only show normal kidney instead of tumour. TNC glows like ICG but is brighter and travels within cells. This project aims to develop TNC into a WT specific dye so that the surgeon can see where the cancer cells are during surgery. Mr Pachl is uniquely positioned to implement the outcomes of this study at a regional, national and international level. Additionally his position as a consultant oncology surgeon at Birmingham Childrens Hospital will facilitate effective transition of this research from the lab directly to patients.
 

Targeting neurodevelopmental pathways in paediatric high-grade gliomas

Paediatric high-grade gliomas are fast-growing brain tumours that occur in children and adolescents. Unfortunately, no effective therapies are currently available for these patients and surgery is rarely possible because the tumour cells are intermingled with important healthy cells of the brain. In this project, we will use a combination of patient tissue samples and lab-grown tumours to investigate how malignant cells invade
healthy brain areas, and whether preventing this ability can alleviate tumour-related symptoms. Ultimately, we hope that the project will inform the development of new therapies that can effectively halt tumour growth without damaging healthy brain cells or any other part of the body.

The burden of rare pathogenic germline variants in neuroblastoma

Our team is on a mission to understand why some children are more likely to develop a type of cancer called neuroblastoma. Just like every person has unique features like eye color and height, we all have a unique set of genes that can affect our health. Sometimes, changes in our genes can make us more susceptible to certain diseases, including cancers. We are using a technique called whole exome sequencing that allows us to analyze all genes in one experiment. By comparing the genes of children with neuroblastoma to those of healthy individuals, we aim to uncover the hidden changes that may increase the risk of developing this disease. Our goal is to use this knowledge to guide families on how to better monitor and protect their children's health, potentially leading to earlier detection and more effective treatments for neuroblastoma.

The role of CaMK1D in the formation of the tumour microenvironment in paediatric diffuse large B cell
lymphomas

Lymphomas are types of blood cancer which affect children and are treated with multiple chemotherapy drugs in combination. Despite high chances of survival for many children, 10-15% will not respond to current treatments and are incurable. For children who are cured, the current treatments have both immediate and long-term side effects, which can be life-changing. There is an increasing need for new treatments which are more targeted, thereby reducing these side effects without reducing survival rates. In addition to cancerous cells various other cells surrounding tumour nest can play a critical role in the development and progression of lymphomas. However, the composition and general organisation of tissue which surrounds the tumour nest in lymphomas in children is currently unknown. In the proposed work we would like to address this by identifying different cells using specific molecular markers. We will also employ an advanced protocol to create a visual map of how different cell types are positioned relative to one another in cancerous tissues. Finally, we will examine how the abundant presence of a protein called CaMK1D affects the cellular architecture of the cancerous tissues.

Understanding the Genetic Causes of Wilms Tumour

All humans have naturally occurring variation in their DNA. Most variants do not affect health but some can. Children that are born with a faulty variants in an anti-cancer gene are more likely to develop cancer in childhood. Our team compared variants between children who developed Wilms Tumor (WT) which the most common childhood kidney cancer, with people who did not have WT. We found genetic variants which are overrepresented in WT patients, and are now trying to understand how these variants can affect the expression of genes and potentially lead to cancer. We use next generation sequencing to read the DNA and study its epigenetics – these are the modifications made to the DNA to change how active it is. For example, one variant we have reduces expression of one gene but the same variants may also control the expression of its neighbouring gene. We hope to identify exactly which genetic variant changes which gene, and how this gene expression change leads to cancer. Understanding this variant-cancer connection can help identify children who are likely to develop cancer, and can inform tumour diagnosis and treatment planning.

Unraveling genes and mechanisms underlying relapse of T-cell acute lymphoblastic leukemia 

We aim to provide novel knowledge on the genes and biological processes which drive the survival advantage of T-ALL cells and their evolution from diagnosis to relapse. We will use two state of the art methods: 1/ single- cell sequencing of the transcriptome (scRNA-seq) of T-ALL cells obtained from patients’ samples at diagnosis and at relapse to investigate clonal heterogeneity and evolution, 2/ genome-wide dropout screen using CRISPR/Cas9 method to identify genes essential for leukemic cells to survive. We will select several genes and verify their importance for T-ALL cells – we will activate or inactivate the expression of these genes in T- ALL cell lines and investigate, how these changes impact the ability of leukemic cells to proliferate and survive. Finally, we will use bioinformatics approaches and publicly available data generated from T-ALL samples to verify, if the alterations of genes’ expression observed in our study, are in fact related to the occurrence of T- ALL relapse in other groups of patients.

The ultimate goal of the project is to unravel the mechanisms of T-ALL relapse and to pave the way towards precise identification of high risk patients, which will facilitate the determination of the best treatment options to prevent leukemia relapse and improve the survival of T-ALL patients.

Validating an immunophenotype of chemotherapy resistance in childhood B-ALL – towards tailored
treatment and improved outcomes

B-acute lymphoblastic leukaemia (B-ALL) is the most common cancer in children. Although current cure ratesare around 90% they are achieved through treatment with highly toxic chemotherapy drugs which have long-term, debilitating side-effects. Furthermore, the outlook for the 10% of children whose disease returns is dismal, with only half surviving a further 5 years or more.

This research is focussing on identifying markers of chemotherapy resistance that can be successfully added to the existing panel of markers used in leukaemia diagnostics and to test the ability of this expanded panel to identify resistant cells within the leukaemia. Multiple samples will be used to help refine the panel to the most informative markers.