Improving outcomes for obese children with Acute Lymphoblastic Leukaemia (ALL): a clinical collaboration to understand the influence of obesity on treatment success.

Dewhurst, Toni ORCID: https://orcid.org/0000-0002-3966-7836 2022, Improving outcomes for obese children with Acute Lymphoblastic Leukaemia (ALL): a clinical collaboration to understand the influence of obesity on treatment success. , PhD thesis, University of Salford.

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Abstract

Cancer Research UK has reported that obesity is the second highest risk factor for developing cancer after smoking. Studies suggest that almost three quarters of people are expected to be overweight by 2035. Children with ALL who are obese at diagnosis are less likely respond to standard cancer treatment, it is more difficult to achieve a complete remission in obese children, they are subject to higher minimal residual disease risk, poorer event free survival and increased risk of metabolic syndrome and cardiovascular disease later in life This work has been designed to identify changes in adipokine profiles at diagnosis and after the intense phase of induction therapy to investigate if dysregulated adipokine profiles contribute to weight gain and MRD risk. To achieve this weight status and BMI was recorded and blood plasma was tested using human adipokine arrays at diagnosis and following induction therapy to establish if these changes correlated with weight gain or MRD risk. We have shown that MRD risk status at the end of induction therapy is associated with lower weight rather than weight gain. We have identified a number of adipokines linked to MRD risk and weight gain in our patient cohort, these include Leptin, IL-8, pref-1, endocan and adiponectin in weight gain. Also, resistin, serpin A12, IGFBP4, cathepsin-S and Angiopoetin-2 in MRD risk. We have shown that leptin, IL-8, serpin A12 and angiopoietin-2 have a protective effect when incubated with the Molt4 ALL cell line and that resistin does not offer this protection. Further experiments with leptin confirmed the activation of the PI3K/Akt pathway which is a shared pathway with the other adipokines of interest along with the JAK/STAT pathway. Leptin was unable to change the sensitivity of the chemotherapy drugs alone this may suggest that targeting single adipokines may not be the best course of future treatment stratification. Inhibitors of the PI3K/Akt pathway or the JAK/STAT pathway could be treatment options for adipokines highlighted in this study. Future treatment options that show promise could include activators of AMPK like metformin, Bcl-2 inhibitors or small molecule inhibitors that target common pathways of chemoresistance which include autophagy, upregulation of drug efflux pumps or the UPR network. It is clear that more research is needed in these areas in the hope to improve outcomes for obese, overweight and MRD risk patients and to develop kinder drug treatments for paediatric ALL patients.

Item Type: Thesis (PhD)
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Funders: Kidscan- Childrens Cancer Research
Depositing User: Toni Dewhurst
Date Deposited: 12 Apr 2022 15:24
Last Modified: 12 May 2022 02:31
URI: http://usir.salford.ac.uk/id/eprint/63254

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