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

• 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
• 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

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.

肥胖是一项全球健康挑战，可增加从多种类型的发展和死亡的风险 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，诊断时肥胖的儿童的反应不佳的可能性是他们的瘦同龄人的两倍以上 诱导疗法，最终因其疾病复发和死亡。因此，肥胖儿童的生存 随着B-ALL人口的更广泛的限制，尚未改善。 B-all化学疗法诱导了许多 非肥胖儿童的生理变化与肥胖相同，从而使瘦小的孩子甚至放置 有抗化疗的风险。在一系列临床和实验室模型中，应有的化学抗性 发现肥胖的生理学可能是可逆的。最近的I阶段试验证明了原理证明 通过饮食和体育锻炼实现的卡路里，脂肪和葡萄糖限制（CFGR）的组合， 可以逆转肥胖引起的化学抗性。试验表明，CFGR可以集成到小儿 B-所有诱导方案，最重要的是，CFGR降低了约71％ 诱导结束时疾病（EOI MRD）； EOI MRD是B-的最重要的预测指标之一 全部。在研究CFGR功效的基础机制时，发现胰岛素是可能的关键 化学抗性的引发剂和脂联素，这是B-ALL中胰岛素效应的激素反应不足。 该提议的中心假设是CFGR将通过改进来减少B-All的MRD 通过降低循环胰岛素并增加脂联素，从而降低信号传导，从而化学敏感性 在所有促生物/抗凋亡途径中。这项研究的长期目标是逆转肥胖引起的 化学耐药性以提高B-all的生存。在此提案中，CFGR功效将在A中评估 通过小儿白血病联盟进行的随机，多中心II期试验。瘦和肥胖 患有高风险B-ALL的注册患者将接受或不使用CFGR的诱导化疗四个星期。 在AIM 1中，通过肥胖状态和开始白血病负担将患者随机分为地层（白细胞计数） 将接受一次性营养和运动教育（控制部门）或教育以及CFGR（干预 手臂）。主要终点将减少MRD和脂肪质量的变化。次要终点将评估 依从性，健身，运动功能，毒性和生活质量。在AIM 2中，循环胰岛素和 将探索脂肪素对肥胖的化学耐药性和CFGR功效。肥胖生理的变化 CFGR将通过激素，细胞因子和代谢组学评估。肥胖生理学的相反影响 将测量Akt，MTOR和RAF/RAS化学固定途径的细胞内激活的CFGR 使用质量细胞仪。该试验的结果将证明CFGR有效改善疾病反应 并洞悉肥胖诱导的B-all化学耐药性的机理，可能导致A 治疗这种致命疾病的范式转移。