Targeting obesity to improve survival from childhood acute lymphoblastic leukemia

肥胖是一个世界性的健康挑战，它增加了发展和死于多种类型 癌症。B细胞急性淋巴细胞白血病(B-ALL)是儿童最常见的癌症。尽管情况有所改善 治愈率，被诊断为肥胖的儿童反应差的可能性是瘦同龄人的两倍多 到诱导治疗，并最终复发并死于他们的疾病。因此，肥胖儿童的存活率 没有与更广泛的B-ALL人口同步改善。B-ALL的化疗诱导了许多 非肥胖儿童的生理变化与肥胖者相同，因此即使是苗条的儿童 面临化疗耐药性的风险。在一系列临床和实验室模型中，化疗耐药都是 肥胖的生理学被发现是潜在的可逆的。最近的一项第一阶段试验证明了原则的证明 通过饮食和体力活动实现的卡路里、脂肪和葡萄糖限制(CFGR)的组合， 可以逆转肥胖引起的化疗耐药性。试验表明，CFGR可以整合到儿科 B-ALL诱导方案，最重要的是，CFGR将最小残留率降低了~71% 诱导末期疾病(EOI MRD)；EOI MRD是B-T细胞复发的最重要预测指标之一 全。在研究CFGR疗效的潜在机制时，发现胰岛素可能是一个关键 化疗耐药的启动者，以及脂联素，一种被低估的激素，在B-ALL中对抗胰岛素的作用。 这一建议的中心假设是CFGR将通过改善以下各项来降低B-ALL的MRD 降低循环胰岛素和增加脂联素的化疗敏感性，共同减少信号转导 在所有促进生存/抗凋亡的途径中。这项研究的长期目标是逆转肥胖引发的 化疗耐药以提高B-ALL的存活率。在这份提案中，CFGR的效果将通过 通过儿童白血病联盟进行的随机多中心II期试验。又瘦又胖 登记的高危B-ALL患者将接受为期四周的诱导化疗，无论是否有CFGR。 在目标1中，患者根据肥胖状况和开始的白血病负担(白细胞计数)随机分成不同的组 将接受一次性营养和运动教育(控制组)或教育加CFGR(干预 手臂)。主要终点将是MRD的减少和脂肪质量的变化。次要终端将评估 坚持、健康、运动功能、毒性和生活质量。在目标2中，循环胰岛素和 将探讨脂联素对肥胖化疗耐药和CFGR的疗效。肥胖生理学的变化 CFGR将通过激素、细胞因子和代谢组学进行评估。肥胖生理学的反面效应 和CFGR对AKT、mTOR和Raf/Ras耐药通路细胞内激活的影响 使用质量细胞术。这项试验的结果将证明CFGR在改善疾病反应方面的有效性 并为肥胖诱导B-ALL化疗耐药的机制提供了洞察力，可能导致 治疗这种致命疾病的范式转变。

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.