Title: Treatment resistance in B-cell Acute Lymphoblastic Leukaemia: A question of genetics, microenvironment or the interplay between the two?
Funder: Cancer Research UK

Abstract: Background Although almost all patients with B-cell Acute Lymphoblastic Leukaemia (B-ALL) achieve remission after initial chemotherapy, the remaining sub-microscopic disease proves very challenging to eradicate. Most children with B-ALL are cured but require prolonged chemotherapy over several years, whereas most adults die of the disease despite similar excellent initial response rates. Recent murine models studies suggest chemo-resistant B-ALL cells are not genetically distinct from the treatment-sensitive bulk population. Instead, treatmentresistant cells reside in a protective ‘niche’ with mesenchymal stromal cells (MSCs). I hypothesise that both B-ALL genetic sub-type and chemotherapeutic drugs used are critical to niche formation and that leukaemic cells within the niche have altered mitochondrial metabolism, favouring chemo-resistance. Aims 1. Characterise chemo-resistant niche formation in a B-ALL murine xenograft model across different genetic subtypes. 2. Determine if chemo-resistant B-ALL cells within the niche have altered mitochondrial function. 3. Identify strategies effectively targeting treatment-resistant B-ALL cells. Methods Aim 1 I will study B-ALL niche formation using intravital two photon and confocal imaging of murine calvarium bone marrow in NOD-scid IL2Rgammanull (NSG) mice. I will use cell lines and patient derived xenograft models with the relevant genetic abnormalities in NSG mice with different stromal cell reporters before and after chemotherapy. Assessment of niche formation will include spatial positioning, tracking of duration and nature of interactions of B-ALL cells relative to stromal cells using quantitative image analysis. Aim 2 I will use murine models to determine if mitochondrial metabolism of B-ALL cells differs across genetic sub-types, before and after chemotherapy. I will focus on central carbon metabolism analysis through targeted metabolomics using stable isotope labelling experiments in vivo. The findings will be interrogated through in vitro niche models using human MSC with B-ALL cells. Aim 3 I will explore therapeutic agents capable of overcoming niche-mediated protection of treatment-resistant B-ALL cells in vitro and in vivo. This will include two distinct approaches: inhibiting structural niche formation or targeting vulnerabilities in mitochondrial metabolism treatment-resistant B-ALL cells. I will combine novel agents with conventional drugs currently used in B-ALL treatment. Impact This project will provide vital information about how the minority of cancer cells evade treatment. It uniquely links the ability to visualise chemo-resistant cancer cellstroma interaction in vivo and determine how cancer cell metabolism is altered as a consequence. This is likely to lead to identification of novel treatments to either target the stroma-cancer cell interaction or altered metabolism of chemo-resistant cancer cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS