Towards superior metabolic starvation of T-ALL for clinical treatment innovation

Primary supervisor: Bela Wrench, Queen Mary University of London

Secondary supervisor: Paul Maciocia, UCL

Project

Transformations in acute lymphoblastic leukaemia (ALL) therapy have primarily benefited the most prevalent disease subtype, B lineage-ALL, leaving a rare cohort of T lineage patients (20%) relatively neglected for new therapies. T-ALL disease relapses are among the most aggressive and chemo-refractory [1], particularly in young adults and teenagers, highlighting the need for novel modes of treatment. Whilst metabolic dependencies represent a hallmark of T-ALL, efforts to exploit the T-ALL metabolome have proved elusive beyond discrete targeting of asparagine metabolism.

Auxotrophic tumours are characterised by their reliance on exogenous sources of specific nutrients (e.g., amino acids) for cellular growth, owing to intrinsic deficiencies in biosynthetic pathways. This feature renders them therapeutically targetable to nutrient depletion strategies. In the context of arginine auxotrophy, we have identified a novel therapeutically tractable pathway with widespread potential for T-ALL through co-dependency mapping and synthetic lethality network analysis of cellular responses to arginine starvation induced by the therapeutic enzyme arginine deiminase (ADI) [2,3].

This systems-level analysis demonstrates that activation of C/EBPβ driven transcriptional programmes constitutes a central mechanism mediating the cellular adaptive response to arginine deprivation uncovering a novel synergistic vulnerability. We now aim to translate this knowledge into preclinical development of therapeutic strategies that disrupt this intrinsic adaptive arginine starvation response for application in T-ALL.

To address this goal the student will (i) perform a rigorous evaluation of translational biomarkers for metabolic stratification of T-ALL to predict ultimate sensitivity to arginine depletion (ii) Test their robustness as functional response predictors in vivo using clinical-grade C/EBPβ and arginine modulators, assessed together or in combination with standard therapies (iii) Assess application in novel emerging CAR-T treatment pathways for refractory/relapsed T-ALL. Together these work packages will determine how to translate arginine starvation strategies optimally into effective clinical paradigms for T-ALL

Aim 1 Prospective identification of arginine dependant auxotrophic T-ALL using common clinical, pathologic and genomic features

Generalised biomarkers of arginine auxotrophy typically rely on ASS1 gene expression status (specifically low expression) for tumour stratification. However, establishing a clear cut-off threshold remains challenging, leading to significant imprecision in classification. To explore robust alternative approaches, the student will evaluate relationships between common genomic and cell-type features of T-ALL and gene expression auxotrophic markers, including ASS1 and arginine metabolic network genes, using comprehensive clinical trial-linked annotations (RNA-seq, WGS) from the UKALL 14 and UKALL 2011 studies.

The primary objective is to determine whether clinical response predictors of arginine deprivation can provide robust and decisive stratification of the arginine auxotrophic phenotype. In parallel, novel mechanism-informed biomarkers will be explored using hallmarks of C/EBPβ activation patterns determined at the chromatin level. Together, these results will inform approaches for defining the spectrum of arginine-dependent metabolic phenotypes in T-ALL, ultimately guiding personalised arginine deprivation therapeutic strategies.

Aim 2 Perform in vivo targeting of C/EBPβ as a synthetically lethal treatment for ADI-PEG20 targeting of T-ALL arginine auxotrophy.
To functionally validate predictors of arginine-dependent T-ALL tumours (further refined under aim one), we will test the effects of the targeted small-molecule C/EBPβ antagonist Lucicebtide in a selected panel of PDX animal models during ADI treatment. If significant benefit is demonstrated (using survival and tumour burden endpoints) with Lucicebtide combined with ADIPEG20 (pegylated arginase) we will investigate combination treatment with standard chemotherapeutic agents (e.g., dexamethasone, vincristine) to determine whether integration of ADI with conventional therapeutic regimens provides more effective interventions for T-ALL.

Aim 3 Assess applicability in an experimental CAR-T model.

Using CAR-T cells targeting T-cell malignancies, developed and characterised by collaborators at UCL [4], we will comprehensively assess the concept of arginine deprivation as a novel bridging treatment within CAR-T clinical paradigms. Through PDX and syngeneic in vivo models of T-ALL, the student will characterise tumour-specific and CAR-T-linked response outcomes, benchmarking these against metabolic pharmacodynamics. This will include multi-dimensional analysis of CAR-T expansion, persistence, and T-cell phenotypes (memory and effector populations) to evaluate the potential therapeutic benefit of incorporating arginine deprivation as a bridging strategy in emerging CAR-T applications for T-ALL.

Candidate background

The studentship is suitable for those interested in cross-disciplinary research exposure and practical experience in the translational research pipeline for emerging novel biological and cellular therapies with unique opportunities to develop skillsets in bioinformatic data analysis.

Potential Research Placements

1. Gabriella Ficz, Barts Cancer Institute, Queen Mary University of London
2. Amy Kirkwood, Clinical Trials Centre, UCL
3. Paul Maciocia, Cancer Institute, UCL

References

1. JA Whitlock et al. Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR). Pediatr Blood Cancer, 69 (11) (2022), Article e29901
2. MJ Austin, L Halim, F Miraki-Moud, D Taussig, J Bomalaski, J Maher, J Gribben, P Szlosarek and B Patel. Priming Death Receptor Mediated Apoptosis with Arginine Starvation Sensitises Arginine Auxotrophic B-ALL to CAR-T. Blood. Volume 138, Supplement 1, 23 November 2021, Page 2787.
3. MJ Austin, L Halim, F Miraki-Moud, D Taussig, J Bomalaski, J Maher, J Gribben, P Szlosarek and B Patel. Target cell metabolic stress promotes “cytokine-efficient” chimeric antigen receptor t-cell mediated cytolysis of acute lymphoblastic leukaemia. European School Haematology 2024.
4. PM Maciocia et al. Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia. Blood 2022 Jul 7;140(1):25-37.