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. 

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

1) What is this research about? 

This research is focused on a specific type of childhood blood cancer called Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL). Scientists are investigating a subtype called "CML-like Ph+ALL," which seems to share features with another leukaemia called chronic myeloid leukaemia (CML). The goal is to understand if these cases represent a range of diseases rather than just one, by studying the cells at a very detailed level using advance single-cell technology. 

2) Why is it important? 

Ph+ALL usuallt affects more mature white blood cells, while CML affects immature stem cells in the bone marrow. Recent studies suggest that some children's Ph+ALL might have stem cell involvement, similar to CML, which could explain why some patients have worse outcomes and relapse after treatment. Understanding these differences is crucial because it may change how doctors diagnose and treat these patients, potentially leading to better survival rates. 

3) What are the researchers doing? 

The researchers are using a cutting-edge method called CITEseq, which allows them to study individual cells' genes and surface proteins. They are analysing bone marrow samples from children with Ph+ALL to identify different sub-populations of cancer cells, especially focusing on cells carrying the BCR::ABL1 genetic abnormality. They will also test if these cells behave like leukaemia stem cells that can resist treatment. This involves growing cells in the lab and checking their ability to survive and multiply. 

4) How could this help patients in the future? 

By identifying which patients have CML-like form of Ph+ALL and understanding the biology behind it, doctors could tailor treatments more effectively. This might include using therapies similar to those for CML or developing new strategies to target the stubborn stem cells driving the disease. Ultimately, this research aims to reduce relapses and improve long-term outcomes for children with this challenging form of leukaemia. 

ALLTogether team science – improving treatment for drug resistant T-cell Acute Lymphoblastic Leukaemia(T-ALL)

1) What is this research about? 

This research is focused on T-cell Acute Lymphoblastic Leukaemia (T-ALL), a rare but aggressive type of blood cancer in children, teenagers and young adults. While most patients are cured with current treatments, some do not respond to therapy or relapse later, and only 2-3 out of 10 of these children survive. The project aims to understand why some T-ALLs resist treatment and to find new, more effective therapies. 

2) Why is it important? 

For patients with relapsed or drug-resistant T-ALL, treatment options are extremely limited. Unlike other types of leukaemia, there are currently no reliable genetic markers to predict which patients are at highest risk. By combining expertise from 14 countries across Europe, this project will collect enough patient samples to study the disease in depth. This could pave the way for earlier identification of high-risk patients and new targeted treatments that save more young lives. 

3) What are the researchers doing? 

• collecting leukaemia cells from children in the ALLTogether clinical trial (with consent from families)
• growing these cells in specially designed laboratory models, so that enough material is available for testing 
• analysing the cells at the DNA, RNA, protein, and signalling levels to uncover what drives drug resistance. 
• using artificial intelligence ("Digital twin" computer models) to simulate the disease and predict the best treatment strategies.
• testing existing and experimental drugs in the lab to see which combinations are most effective 
• creating a shared European resource of patient samples and data that other researchers can use to accelerate discoveries. 

4) How could this help patients in the future? 

This research could help identify which patients are likely to relapse earlier, so doctors can adapt treatment plans in time. It may also uncover new drugs targets and test medicines that could be rapidly moved into clinical trials. Ultimately, this project aims to increase survival for children and young people with drug-resistant T-ALL and bring personalised, less toxic treatments to the clinic faster.  

Near Infra-red fluorescence in Wilms tumour organoids

1) What is this research about? 

This research is about developing a way to make surgery for Wilms tumour (a type of kidney cancer in children) safer, more accurate, and more effective. During surgery, surgeons cannot always see all areas of cancer, meaning that tiny clusters of tumour cells may be left behind, or sometimes, healthy tissue may be removed unnecessarily. The research team is creating special flourescent dyes that make Wilms tumour cells "grow" under near-infrared light, allowing surgeons to see exactly where the cancer is during the operation. 

2) Why is it important? 

Surgery is the main treatment for Wilms tumour, but hidden cancer cells that remain after surgery can cause relapse, which is often difficult to treat. By helping surgeons identify and remove every cancer cell while preserving healthy kidney tissue, this project could reduce relapse rates and improve survival outcomes for children. A tumour-specific glowing dye would be a major step forward in making cancer surgery more precise and less risky. 

3) What are the researchers doing? 

The research team brings together experts in flourescent chemistry, surgery, organoid biology, and genomics, including Dr Max Pachl, a consultant oncology surgeon at Birmingham Children's Hospital. His clinical expertise will ensure that discoveries made in the lab can be rapidly and safely translated into real-world patient care. 

They will: 

• Grow "mini-tumour" (organoids) from Wilms tumour samples taken during surgery. 
• Test two dyes: Indocyanine Green (ICG), which is safe but not tumour-specific, and triazole-N-cyanine (TNC) dyes,which are brighter and can enter tumour cells more effectively.
• Develop new, Wilms tumour-specific versions of TNC by linking them to markers found only on tumour cells. 
• Examine under microscopes how well these dyes highlight cancer cells compared to normal kidney tissue. 

4) How could this help patients in the future? 

If successful, this research could lead to the first Wilms tumour-specific flourescent dye for surgery.This would help surgeons "see" cancer during operations, remove all tumour tissue, and spare as much healthy kidney as possible. As Dr Pachl is both a leading surgeon and part of this research team, the findings can be quickly translated from the laboratory to the operating theatre, benefitting children in Birmingham and beyond. In the long term, this approach could also be adapted for other childhood and adult cancers. 

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

1) What is this research about? 

This research is exploring a rare form of children's leukaemia called B-cell acute lymphoblastic leukaemia (B-ALL), where cancer cells have unusual numbers of chromosomes. Normally, more chromosomes (hyperdiploidy) suggest a better prognosis, while fewer chromosomes (hypodiploidy) often mean a tougher outlook. Some children have both types of cells at the same time, called biclonal B-ALL. By studying how these different cancer cells interact and evolve, we aim to understand the disease better. 

2) Why is it important? 

Understanding how these two types of leukaemia cells behave together can reveal why some cancers resist treatments or come back after therapy. These rare cases offer a unique opportunity to learn about the competition or cooperation between cancer cells. Insights from this research could help scientists identify key genetic changes that drive disease progression, ultimately improving treatments strategies for children with B-ALL. 

3) What are the researchers doing? 

Researchers will study leukaemia cells from children with biclonal B-ALL using advanced genetic techniques. They will amplify these rare cells in spacially bred mice that can host human leukaemia cells, allowing them to observe the disease in a living system. Techniques like single-cell multi-omics, long-read DNA sequencing will help scientists map the gentic and protein changes in each cell. By comparing cells before and after amplication, they can detect biases or patterns in the disease's development. All animal experiments follow strict ethical guidelines to ensure welfare and minimise the number of animals used. 

4) How could this help patients in the future? 

By understanding the genetic blueprint and interactions of these rare leukaemia cells, researchers hope to identify new targets for treatment and improve ways to predict disease progression. This knowledge could lead to more effective, personlised therapies for children with B-ALL, increasing the chances of recovery and reducing the likelihood of relapse. Ultimately, the goal is to give patients a brighter and healthier future.   

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

1) What is this research about? 

This research focuses on T-cell acute lymphoblastic leukaemia (T-ALL), a type of blood cancer that frequently affects children. While chemotherapy can treat many patients, around 15% experience relapse because their leukaemia cells resists treatement. Relapsed T-ALL is very difficult to treat and often deadly. We aim to understand the biological mechanisms that allow T-ALL cells to survive therapy and evolve from diagnosis to relapse. 

2) Why is it important? 

Currently, there are no reliable genetic markers to predict which patients are at high risk of relapse. Without this knowledge, doctors cannot tailor treatments to prevent recurrence, and children may undergo ineffective therapies with serious side effects. Undertsanding how leukaemia cells survive and adapt could help identify high-risk patients early and lead to more effective treatments. 

3) What are the researchers doing? 

The researchers will use two advanced methods: 

• Single-cell RNA sequencing (scRNA-seq) : This will examine individual leukaemia cells from patients at diagnosis and relapse to reveal differences in gene activity and clonal diversity. 
• CRISPR/Cas9 genome-wide screens : These experiments will identify genes essential for leukaemia cell survival. Selected genes wll be activated or inhibited in T-ALL cell lines to test how they influence cell growth and survival. 

Additionally, public datasets from other T-ALL patients will be analysed to confirm whether the identified genes are associated with relapse in larger patient groups. 

4) How could this help patients in the future? 

This research could lead to precise identification of children at high risk of relapse and guide personalised treatement strategies to prevent recurrence. Ultimately, it aims to improve survival, reduce unnecessary side effects, and provide new targets for therapies against T-ALL. 

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

1) What is this research about? 

This research aims to understand why some childhood cancers retrun after treatment and stop responding to standard therapies. Sceintists are investigating both genetic and non-genetic factors, including how tumours evolve over time and interact with the immune system. To study these processes, they use patient-derived models such as tumour cells grown in the laboratory, 3D mini-tumours called organoids, and patient-derived xenografts (PDXs), where human tumour tissue is grown specifcally-designed immunocompromised mice. These models closely reflect a child's actual tumour and provide powerful tools to test new treatments in conditions that mimic the human body. 

2) Why is it important? 

Cancer is the leading disease-related cause of death in children aged 1 - 15 years. Most deaths occur when the cancer returns after treatment, often in more aggressive and drug-resistant form. Current treatments cannot always predict which therapies will work best for each child, especially in rare or high-risk cancers. By uncovering the mechanisms driving relapse and treatment failure, this research aims to improve personalised treatement strategies and increase long-term survival. 

3) What are researchers doing? 

• Developing patient-derived models from fresh frozen tumour samples collected at diagnosis, surgery or relapse 
• Using these models to identify which drugs are most effective for individual tumours 
• Studying how tumours interact with the immune system to inform immunotherapy approaches 
• Using PDX models responsibly under strict ethical standards to minimise animal use and ensure high levels of welfare 

4) How could this help patients in the future? 

• Improve the ability to match chidlren with treatments that are more likely to work for their specific tumour 
• Identify genetic and biological markers that signal treatment resistance or relapse earlier 
• Provide safer and more accurate ways to test new drugs before they reach clinical trials 
• Accelerate progress toward more personalised and effective therapies for children with rare, relapsed or high-risk cancers. 

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

1) What is this research about? 

This research focuses on understanding why some childhood cancers, like neuroblastoma and rhabdomyosarcoma, relapse or resist treatment. Even when initial therapy seems successful, certain cancers can survive and return, making them difficult to treat. Scientists believe that beyond genetic changes, cancer cells can adapt through a process called cellular plasticity, changing their behaviour without altering their DNA. This project aims to study these changes in individual cancer cells and identify molecular biomarkers that could predict which patients are at risk of relapse. 

2) Why is it important? 

Although many childhood cancers have good outcomes, patients whose tumours progress or relapse often face very limited options and poor survival rates. Understanding how cancer cells adapt, and resist therapy is essential to improving risk predictions, designing better treatments, and giving children a better chance of cure. By exploring non-genetic mechanisms like cellular plasticity, researchers hope to uncover new ways to anticipate relapse and imrpove personalised care.   

3) What are the researchers doing? 

The team will use high-resolution single-cell techniques to examine patients samples from neuroblastoma, rhabdomyosarcoma and hepatoblastoma cases. They will analyse both early diagnostic biopsies and relapsed or metatstic tumours to identify the epigenetic changes that allow cancer cells to adapt. Functional screens will help pinpoint vulnerabilities in these plastic cancer cells. The goal is to create a dynamic platform that links molecular markers of plasticity with patient outcomes and potential treatments, providing personalised therapy strategies. 

4) How could this help patients in the future?

By identifying biomarkers of cellular plasticity, doctors could predict which children are most at risk of cancer relapse and tailor treatment strategies accordingly. This research could lead to innovative therapies that target the adaptive behaviours of cancer cells, rather than just their genetic mutations. In the long term, it could make treatment more individualised, increase survival rates, and offer better outcomes for children with high-risk or relapsed cancers. 

Understanding the Genetic Causes of Wilms Tumour

1) What is this reserch about? 

This research is investigating how changes in our DNA, called genetic variants, can increase the risk of Wilms Tumour (WT), the most common kidney cancer in children. While most genetic differences have no effect on health, some can influence how genes work. Our team has identified two regions in the genome where certain variants are more common in children with WT. We are now studying how these variants might change gene activity and contribute to cancer development. 

2) Why is it important? 

Understanding the connection between specific genetic variants and WT can help explain why some children develop this cancer while others do not. Currently, it is not clear how many of these variants affect genes that control cell growth or repair, and identifying these links could improve early detection, diagnosis, and personalised treatment strategies for children with WT. 

3) What are the researchers doing? 

The researchers are using advanced techniques to map the activity of genes in WT tissue. They are looking at "epigentic" changes, chemical modifications that control how active genes are, using next-generation sequencing. They are also studying how DNA regions interact with each other in three dimensions, which helps identify which genes are being controlled by the risk variants. Finally, the team plans to perform experiments that alter these variants to see how they affect gene activity, helping pinpoint exactly which variants are responsible for increasing cancer risk. 

4) How could this help patients in the future? 

By understanding how specific genetic changes cause WT, doctors could one day identify children at higher risk before cancer develops. This knowledge could also guide treatment decisions by revealing which genes drive the cancer in each patient. Ultimately, the research could lead to more accurate screening, earlier diagnosis, and therapies tailored to a child's unique gentic profile, improving outcomes and survival for children with Wilms Tumour. 

The burden of rare pathogenic germline variants in neuroblastoma

1) What is this research about? 

This study is looking for rare inherited genetic changes that may make some children more likely to develop neuroblastoma, a type of childhood cancer that starts in nerve tissue. By studying the complete set of genes (known as the exome) in children with neuroblastoma and comparing them to those in healthy individuals, researchers hope to uncover hidden differences that could explain why certain children are more at risk. 

2) Why is it important? 

Neuroblastoma is the most common solid cancer found outside the brain in children, but surivival rates remain low for many patients. Discovering which genetic changes increase the risk could help doctors identify children at risk earlier, offer more personalised treatement options, and provide better guidance to families. Some of these genetic changes may even point to existing drugs, such as PARP inhibitors, that could be used in new ways to treat the disease.

3) What are the researchers doing? 

The team will gather DNA samples from around 1,600 children with neuroblastoma and compare them to over 4,000 samples from people without the disease. Using a powerful technique called whole exome sequencing, they will scan all genes for rare, harmful changes. Advanced computer analysis will help them to pinpoint which genes are more likely to carry these changes in children with neuroblastoma. The study will also look at how these genetic differences affect treatment response and survival. 

4) How could this help patients in the future? 

 If the research finds genetic changes that raise the risk of neuroblastoma, this knowledge could be used to develop screening tools for at-risk children, guide treatment choices, and inform genetic counselling for families. It may also highlight new treatment targets, paving the way for more effective and less toxic therpies for children facing this challenging cancer. 

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.

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.

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 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.

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.