Our goal is to revolutionise central nervous system directed therapy for childhood leukaemia.
Our research aims to address the two major barriers to progress in the field:
- 1) an incomplete understanding of the key biological mechanisms underlying ALL survival in the CNS microenvironment.
- 2) a lack of clinically useful CNS-ALL diagnostic and prognostic biomarkers.
As well as this we are interested in finding out why only some children get neurotoxicity and if there are any ways we can prevent or reduce the side-effects of our current treatments for CNS leukaemia.
Theme 1: Understanding the biology of CNS leukaemia
Figure 1 illustrates potential models for the relationship between bone marrow and CNS leukaemic clones. Our laboratory was the first to provide definitive evidence for model 2. In brief, we established that leukaemic cells freely enter the CNS compartment, without sub-clonal selection, and confirmed that CNS infiltration is highly likely to be present at the time of original diagnosis, even in patients with negative cytology1,2. Therefore, the risk of CNS relapse is determined by the ability to adapt and survive in the CNS niche, rather than by selective entry to the CNS compartment.
Figure 1: Entry to the CNS is a generic property of ALL blasts: For experimental details see Williams et al Blood 2016;217 p1998-2006
Using biological information to develop novel therapeutics:
Following this discovery, we focussed on identifying factors that enable leukemic blasts to survive in the CNS. We have found several promising targets that may be therapeutically targetable:
Use of MEK-inhibitors to treat ras-mutated CNS-ALL
We identified that the cytokine interleukin-15 provides a growth advantage to ALL blasts under nutrient deprived conditions (such as those found in the CNS)via the ras-raf-MEK-ERK pathway3. We then worked with Prof Julie Irving (Newcastle University) and colleagues to identify a potential role for MEK inhibitors in CNS-ALL (Figure 2)4. This data supported a successful bid to CRUK/Astra Zeneca Combinations Alliance for a Phase I/II trial of MEK-inhibitor Selumetinib plus Dexamethasone in adults and children with relapsed-Ras mutated ALL5.
Figure 2: CNS leukaemia is significantly reduced by treatment with the MEK-inhibitor Selumetinib.
Novel Receptor Targets
Working in collaboration with colleagues from Ulm, Germany, we have identified CD79a and IL7Ralpha as novel CNS-ALL drug targets6,7. This has supported preclinical drug development by Biotech companies.
With Dr Frederik van Delft (Newcastle University) we have shown that Dasatinib plus Dexamethasone are highly effective against T-cell CNS-ALL8. Phase I/II trials are in preparation.
Targeting Metabolic vulnerabilities
CNS-ALL blasts reside in the leptomeninges, bathed in CSF which is extremely low in nutrients and oxygen. Since leukaemic cells need building blocks and energy to survive and proliferate, and CSF nutrient supplies are scarce, we hypothesized that metabolic remodelling (flexible adaptation of metabolism according to tissue location and environmental conditions) would occur. Work from our laboratory9,10 confirmed profound transcriptional adaptation to the CNS niche dominated by metabolic genes highly-enriched for lipid and cholesterol biosynthesis (Figure 3). We have provided proof of concept that stearoyl co-A desaturase (SCD) and cholesterol biosynthesis are clinically relevant targets in CNS-ALL. We are now extending these observations to understand how best to develop novel therapeutics which are less toxic and more effective than our current treatments.
Figure 3: CNS-ALL shows upregulation of lipid and cholesterol biosynthesis, and increased expression of cholesterol synthesis genes is associated with CNS relapse in patients.
1. Bartram J, Goulden N, Wright G, et al. High throughput sequencing in acute lymphoblastic leukemia reveals clonal architecture of central nervous system and bone marrow compartments. Haematologica. 2018;103(3):e110-e114.
2. Williams MT, Yousafzai YM, Elder A, et al. The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood. 2016;127(16):1998-2006.
3. Williams MT, Yousafzai Y, Cox C, et al. Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia. Blood. 2014;123(20):3116-3127.
4. Irving J, Matheson E, Minto L, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood. 2014;124(23):3420-3430.
5. Matheson EC, Thomas H, Case M, et al. Glucocorticoids and selumetinib are highly synergistic in RAS pathway mutated childhood acute lymphoblastic leukemia through upregulation of BIM. Haematologica. 2019.
6. Alsadeq A, Lenk L, Vadakumchery A, et al. IL7R is associated with CNS infiltration and relapse in pediatric B-cell precursor acute lymphoblastic leukemia. Blood. 2018;132(15):1614-1617.
7. Lenk L, Carlet M, Vogiatzi F, et al. CD79a promotes CNS-infiltration and leukemia engraftment in pediatric B-cell precursor acute lymphoblastic leukemia. Commun Biol. 2021;4(1):73.
8. Shi Y, Beckett MC, Blair HJ, et al. Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia. Haematologica. 2020.
9. Savino AM, Fernandes SI, Olivares O, et al. Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment is dependent on Stearoyl CoA desaturase. Nat Cancer. 2020;1(10):998-1009.
Theme 2: Developing Diagnostic and Prognostic Biomarkers for CNS-ALL
Our current tests for CNS leukaemia rely on detecting leukaemia cells free-floating in the fluid around the brain (cerebrospinal fluid, CSF) using a microscope. The problem with these tests is that the majority of leukaemic cells are stuck to the protective cell layers that surround the brain (the meninges), so the free-floating cells are likely to represent only a very small proportion of the overall amount of leukaemia in the CNS.
New technologies can detect tiny amounts of genetic material released from cancers into body fluids (cell-free DNA) and measuring this cell-free DNA can indicate the presence of cancers before they become visible. In addition, it has been shown that levels of cell-free DNA rise prior to clinical relapse of tumours providing an early warning system for impending recurrence.
We are investigating whether we can use cell-free DNA, measured in CSF, to determine the level of CNS leukaemia and also to track how rapidly it responds to treatment. In addition, work in our laboratory has identified a number of small molecules (metabolites) in CSF that seem to indicate the presence of leukaemia, we are now testing how accurate these are on larger numbers of samples. These new tests have a lot of theoretical advantages over existing tests and are likely to be much better at detecting submicroscopic amounts of leukaemia that accurately reflect the overall leukaemia disease burden.
Knowing how much CNS disease is present, and how quickly it responds to therapy, should allow us to determine exactly how much treatment each child needs to completely eradicate all the leukaemia in the CNS.
The current childhood, teenage and young adult ALL trial - ALLTogether1, involves 14 European countries. It includes a scientific sub-study, led by our Glasgow team, called CSF-FLOW. This study is collecting CSF during ALL treatment and will use flow cytometry, metabolomics and proteomics to accurately measure the amount of leukaemia in the CSF and how quickly it responds to treatment. We plan to use this information to identify children with:
- very low amounts of leukaemia in the CSF who might be able to receive less brain-directed chemotherapy (to be tested in a future clinical trial).
- very high amounts of leukaemia in the CSF, or other high-risk features, who might be better cured with different treatment approaches (again to be tested in a future clinical trial)
CSF-FLOW will help us accurately measure leukaemia in the CSF for the first time. We hope it will allow us to revolutionise our approach to treating leukaemia in the brain by adapting the amount of treatment to the risk of leukaemia coming back.
Theme 3: Reducing neurotoxicity in childhood ALL
Most children with acute lymphoblastic leukaemia (ALL) are cured, but treatment is arduous, intensive and causes significant acute and long-term side-effects.
Neurological toxicity is common: about 5-10% of patients suffer an acute neurological serious adverse event and about one-third of survivors have neurocognitive impairment. Despite this, risk-factors for developing neurotoxicity are poorly understood.
To improve neurological outcomes, it is important to routinely evaluate the relative neurotoxicity rates of different treatment approaches, identify individuals at highest risk, and devise evidence-based interventions to reduce or eliminate this disabling complication.
We are currently trying to find out why some children get neurotoxicity and others don’t, as well as whether we can intervene to reduce the occurrence or severity of neurotoxicity. Projects running in the lab include:
The Biomarkers and the discovery of new therapeutic targets for Chemotherapy Associated Neurotoxicity study asks whether simple computer-based programmes, genetic or cerebrospinal fluid (CSF) tests can identify children at risk of brain complications.
In addition, it is investigating whether neurotoxicity is related to a build-up of certain chemicals in the brain that could be blocked by new treatments.
If we can predict patients at risk, we might be able to design interventions (such as brain training programmes or new drugs) to reduce or prevent the damaging effects of chemotherapy on the brain.
The BRAIN (Biomarkers to Reform Approaches to Therapy-Induced Neurotoxicity) study will identify patient and treatment risk-factors for chemotherapy-associated neurotoxicity, and prospectively identify children requiring neuropsychological intervention. It uses state-of-the-art neurocognitive assessment tools, novel toxicity reporting systems and harnesses the unique statistical power of one of the world’s largest childhood leukaemia trials – ALLTogether1. BRAIN is an approved ALLTogether1 sub-study, developed by a UK team of experts in CNS leukaemia (Halsey), Neuropsychology (Thomas), ALL trials (Moppett, Clifton-Hadley) and Biostatistics (Kirkwood).
- To assess the cumulative neurotoxicity of each randomized treatment arm,
- To identify children with neurocognitive impairment for neuropsychology referral
- To develop accurate risk prediction models for adverse neurocognitive outcomes, enabling future targeted interventions.
All children in the ALLTogether trial will be eligible to participate. Acute neurotoxic events will be electronically captured during treatment, chronic neurocognitive impairment will be measured using patient friendly CogState software at the end of treatment. Results will be correlated with treatment and demographic variables to identify risk-factors for adverse outcomes. Results will also be fed into related ALLTogether1 studies using genome-wide association studies for key treatment related toxicities and linked to patient reported outcome measures.
The results of BRAIN will transform our understanding of this serious treatment complication and enable future trials of interventions targeted to at-risk individuals.
The Ponte di Legno Deep Phenotyping-Genotyping Neurotoxicity study
Acute neurotoxicity events, such as stroke-like syndrome/posterior reversible encephalopathy syndrome, remain devastating but rare complications of childhood acute lymphoblastic leukaemia (ALL) treatment. The risk factors and predictors of outcome for these conditions are largely unknown because each individual national trial group sees too few cases to enable in-depth analysis. To tackle this, an international consortium has been formed comprising fourteen national trial groups representing over 20 countries enabling information to be gathered on >1800 cases worldwide.
This project aims to:
- carry out deep phenotyping of these cases to identify clinical features, risk factors and predictors of poor outcome.
- Genotype a discovery cohort of severe cases to identify risk alleles for development of neurotoxicity
- Create and analyse a validation cohort to test whether identified risk alleles can predict neurotoxicity in independent cohorts of children with ALL.
This information is predicted to improve outcome for these patients by:
- identifying modifiable acquired risk factors (such as drug interactions),
- improved prediction of outcomes enabling improved counselling of affected families and provision of appropriate supportive care and
- identifying genetic risk alleles that may enable precision medicine by tailoring therapies according to an individual’s risk of toxicity.
Raising Clinical Awareness
In addition, to these ongoing projects we have published a number of papers to raise awareness of drug interactions and appropriate drug dosing to maximise effectiveness and minimise toxicity of our current CNS-directed therapy1-5.
1. Forster VJ, Bell G, Halsey C. Should nitrous oxide ever be used in oncology patients receiving methotrexate therapy? Paediatr Anaesth. 2020;30(1):9-16.
2. Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C. Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients. Cancer chemotherapy and pharmacology. 2016;78(5):1093-1096.
3. Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C. Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect. Cancer Chemother Pharmacol. 2017.
4. Schmiegelow K, Attarbaschi A, Barzilai S, et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. The Lancet Oncology. 2016;17(6):e231-e239.
5. Wilson R, Osborne C, Halsey C. The Use of Ommaya Reservoirs to Deliver Central Nervous System-Directed Chemotherapy in Childhood Acute Lymphoblastic Leukaemia. Paediatric drugs. 2018;20(4):293-301.
Theme 4: Public Engagement and Patient Involvement
The Halsey lab strongly advocates for patient/parent/public involvement in research.
Presenting our future research plans to the Cancer Research UK (CRUK) Research and Strategy Cancer Insight Panel (CIP) in Nov 2019. Discussions with the panel directly informed our research direction.
The CRUK patient involvement team also helped us set up e-consultations with the CIP and the Children and Young People’s Advisory Panel, on different interventions to reduce neurotoxicity.
Our PPI work is featured as a case study on the CRUK patient involvement toolkit webpages:(https://www.cancerresearchuk.org/sites/default/files/translational_case_study_02.pdf)
A recent funding application for a clinical study included a parent as a collaborator and the PPI lead from Great Ormond Street as a co-applicant.
Public engagement is also very important for us. One of our University of Glasgow Final Honours Biochemistry students has produced a video explaining our research to patients with leukaemia, their parents and the wider healthcare team; (https://officeforrareconditions.org/public-engagement-project/)
Other regular activities include:
- Visiting schools to promote cancer research and science careers.
- Running public engagement activities at Glasgow Science Centre “Science Lates’” events, including the popular “Christmas neurons” event at the Noel Lates evening (2018).