Targeting obesity to improve survival from childhood acute lymphoblastic leukemia

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Obesity is a worldwide health challenge that increases the risk of developing and dying from multiple types of cancer. B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite improved cure rates, children with obesity at diagnosis are more than twice as likely as their lean peers to respond poorly to induction therapy, and eventually to relapse and die from their disease. Thus, survival for children with obesity has not improved in lockstep with the broader B-ALL population. Chemotherapy for B-ALL induces many of the same physiologic changes in non-obese children as those found in the obese, thereby placing even lean children at risk for chemotherapy resistance. In a series of clinical and laboratory models, chemoresistance in ALL due to obese physiology was found to be potentially reversible. A recent Phase I trial demonstrated proof-of-principle that a combination of calorie, fat, and glucose restriction (CFGR), achieved through diet and physical activity, could reverse obesity-induced chemoresistance. The trial showed that CFGR could be integrated into pediatric B-ALL induction regimens, and most importantly, that CFGR reduced by ~71% the rate of minimal residual disease at the end of induction (EOI MRD); EOI MRD is one of the most significant predictors of relapse in B- ALL. In investigating the mechanisms underlying the efficacy of CFGR, insulin was discovered to be a likely key initiator of chemoresistance, and adiponectin, an underappreciated hormone countering insulin effects in B-ALL. The central hypothesis of this proposal is that CFGR will reduce MRD in B-ALL through improving chemosensitivity by lowering circulating insulin and increasing adiponectin, together reducing signaling in ALL pro-survival/anti-apoptotic pathways. The long-term goal of this research is to reverse obesity-induced chemoresistance to improve survival from B-ALL. In this proposal, CFGR efficacy will be evaluated in a randomized, multicenter Phase II trial conducted through a pediatric leukemia consortium. Lean and obese enrolled patients with high-risk B-ALL will receive induction chemotherapy with or without CFGR for four weeks. In Aim 1, patients randomized into strata by obesity status and starting leukemia burden (white blood cell count) will receive either one-time nutrition and exercise education (control arm) or education plus CFGR (intervention arm). Primary endpoints will be reductions in MRD and change in fat mass. Secondary endpoints will assess adherence, fitness, motor function, toxicity, and quality of life. In Aim 2, the contribution of circulating insulin and adiponectin to obese chemoresistance and CFGR efficacy will be explored. Changes in obese physiology by CFGR will be assessed via hormones, cytokines, and metabolomics. The opposing effects of obese physiology and CFGR on intracellular activation of AKT, mTOR, and Raf/Ras chemoresistance pathways will be measured using mass cytometry. Results from this trial will demonstrate efficacy of CFGR to improve disease response and provide insight into the mechanisms of obesity-induced chemoresistance in B-ALL, potentially leading to a paradigm shift in treating this deadly disease.