Targeting obesity to improve survival from childhood acute lymphoblastic leukemia

针对肥胖以提高儿童急性淋巴细胞白血病的生存率

基本信息

批准号：
10686220
负责人：
Etan Orgel
金额：
$ 66.99万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-14 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686220
关键词：
10 year old AKT inhibition Acute Lymphocytic Leukemia Adherence Adult Affect Apoptosis Apoptotic B-Cell Acute Lymphoblastic Leukemia Blood Body Composition Body mass index Branched-Chain Amino Acids Caloric Restriction Calories Cells Cessation of life Chemoresistance Child Childhood Acute Lymphocytic Leukemia Childhood Leukemia Childhood Precursor B Lymphoblastic Leukemia Chronic Clinical Clinical Trials Cooperative Group Cytometry Data Analyses Diagnosis Diet Dietary Intervention Disease Education Enrollment Exercise FRAP1 gene Fatty acid glycerol esters Glucose Goals Health Hormones Hyperglycemia Hyperinsulinism Inflammation Institution Insulin Insulin Resistance Laboratories Lead Leukemia Acute Lymphoblastic Chemotherapy Malignant Childhood Neoplasm Malignant Neoplasms Measures Metabolic Pathway Modeling Motor NF-kappa B Neoadjuvant Therapy Newly Diagnosed Non obese Nonesterified Fatty Acids Nutritional Obesity Outcome Overweight PI3K/AKT Pathway interactions Patients Pediatric Oncology Group Phase Phosphoproteins Phosphorylation Physical activity Physiological Physiology Play Population Population Heterogeneity Proliferating Proto-Oncogene Proteins c-akt Quality of life Randomized Ras/Raf Recurrent disease Refractory Regimen Relapse Research Residual Neoplasm Resistance Risk Role Sampling Series Signal Transduction Testing Therapeutic Thinness Toxic effect Treatment-related toxicity White Blood Cell Count procedure acute lymphoblastic leukemia cell adiponectin arm cancer type cardiovascular fitness chemotherapy comparison control cytokine design efficacy evaluation efficacy testing exercise intervention fitness global health high risk improved insight insulin sensitivity insulin signaling leukemia leukemia relapse leukemia treatment metabolomics minimal risk mortality mouse model nutrition obese patients obese person obesity in children participant enrollment peer phase I trial phase II trial phase III trial pleiotropism primary endpoint receptor relapse prediction relapse prevention response secondary analysis secondary endpoint sedentary lifestyle success treatment arm

项目摘要

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.

肥胖是一项全球性的健康挑战，它增加了多种类型肥胖的发生和死亡风险癌症。 B 细胞急性淋巴细胞白血病 (B-ALL) 是最常见的儿童癌症。尽管有所改善治愈率方面，诊断时患有肥胖症的儿童反应不佳的可能性是瘦同龄人的两倍多诱导治疗，最终疾病复发并死亡。因此，肥胖儿童的生存率并没有与更广泛的 B-ALL 人群同步改善。 B-ALL 化疗会导致许多非肥胖儿童的生理变化与肥胖儿童相同，因此即使是瘦儿童也会出现同样的情况有化疗耐药的风险。在一系列临床和实验室模型中，ALL 的化疗耐药性是由于发现肥胖的生理学可能是可逆的。最近的一期试验证明了原理通过饮食和身体活动实现热量、脂肪和葡萄糖限制（CFGR）的结合，可以逆转肥胖引起的化疗耐药性。该试验表明 CFGR 可以纳入儿科治疗 B-ALL 诱导方案，最重要的是，CFGR 使最小残留率降低了约 71% 诱导结束时疾病（EOI MRD）； EOI MRD 是 B 型复发最重要的预测因素之一全部。在研究 CFGR 功效的机制时，发现胰岛素可能是关键化学耐药性的引发剂和脂联素（一种未被充分认识的激素，可对抗 B-ALL 中的胰岛素作用）。该提案的中心假设是 CFGR 将通过改善 B-ALL 来减少 MRD 通过降低循环胰岛素和增加脂联素来降低化疗敏感性，同时减少信号传导在所有促生存/抗凋亡途径中。这项研究的长期目标是扭转肥胖引起的化学耐药性可提高 B-ALL 的生存率。在本提案中，CFGR 功效将在以下方面进行评估：通过儿童白血病联盟进行的随机、多中心 II 期试验。瘦和肥胖入组的高危 B-ALL 患者将接受为期 4 周的诱导化疗（伴或不伴 CFGR）。在目标 1 中，患者根据肥胖状况和开始白血病负担（白细胞计数）随机分组将接受一次性营养和运动教育（对照组）或教育加 CFGR（干预措施）手臂）。主要终点是 MRD 的减少和脂肪量的变化。次要终点将评估依从性、健身、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性和 CFGR 的功效。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。肥胖生理学的相反影响将测量 AKT、mTOR 和 Raf/Ras 化疗耐药途径细胞内激活的 CFGR 使用质谱流式细胞仪。该试验的结果将证明 CFGR 改善疾病反应的功效并深入了解肥胖引起的 B-ALL 化疗耐药机制，可能导致治疗这种致命疾病的范式转变。