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: 10488577
• 负责人: Etan Orgel
• 金额: $ 69.02万
• 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/10488577
• 关键词: 10 year old; Acute Lymphocytic Leukemia; Adherence; Adult; Affect; Apoptotic; B-Cell Acute Lymphoblastic Leukemia; Blood; Body Composition; Body mass index; Branched-Chain Amino Acids; Caloric Restriction; Calories; Cells; 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; 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; Time; Toxic effect; Treatment-related toxicity; White Blood Cell Count procedure; acute lymphoblastic leukemia cell; adiponectin; arm; base; cancer type; cardiovascular fitness; chemotherapy; cytokine; design; efficacy evaluation; efficacy testing; exercise intervention; fitness; global health; high risk; improved; insight; insulin sensitivity; insulin signaling; leukemia; leukemia relapse; metabolomics; minimal risk; mortality; mouse model; nutrition; obese patients; obese person; obesity in children; peer; phase I trial; phase II trial; phase III trial; pleiotropism; prevent; primary endpoint; receptor; relapse prediction; 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.

肥胖是一个全球性的健康挑战，增加了发展和死于多种类型的疾病的风险。 癌B细胞急性淋巴细胞白血病（B-ALL）是最常见的儿童癌症。尽管改善了 治愈率，诊断时肥胖的儿童比他们瘦的同龄人反应差的可能性高两倍多。 到诱导治疗，最终复发并死于疾病。因此，肥胖儿童的存活率 并没有与更广泛的B-ALL人群同步改善。B-ALL的化疗诱导了许多 非肥胖儿童的生理变化与肥胖儿童相同， 有化疗耐药的风险在一系列的临床和实验室模型中，ALL的化疗耐药性是由于 对肥胖生理的影响被发现是潜在可逆的。最近的一项I期试验表明， 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。该试验表明，CFGR可以整合到儿科 B-ALL诱导方案，最重要的是，CFGR使最小残留率降低约71%， 诱导结束时的疾病（EOI MRD）; EOI MRD是B- 所有.在研究CFGR功效的机制时，发现胰岛素可能是关键 化学抗性的引发剂和脂联素，一种在B-ALL中对抗胰岛素作用的未被充分认识的激素。 该建议的中心假设是，CFGR将通过改善B-ALL中的MRD来降低MRD。 通过降低循环胰岛素和增加脂联素，同时降低信号传导， 在ALL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 化疗耐药性，以改善B-ALL的生存率。在本提案中，CFGR功效将在 通过儿科白血病联盟进行的随机、多中心II期试验。瘦型和肥胖 入选的高风险B-ALL患者将接受四周的诱导化疗，伴或不伴CFGR。 在目标1中，患者按肥胖状态和起始白血病负荷（白色血细胞计数）随机分层 将接受一次性营养和运动教育（对照组）或教育加CFGR（干预组 手臂）。主要终点为MRD降低和脂肪量变化。次要终点将评估 依从性、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性和CFGR的疗效。肥胖生理学的变化， 将通过激素、细胞因子和代谢组学评估CFGR。肥胖生理学的相反影响 将测量CFGR对AKT、mTOR和Raf/Ras化学抗性途径的细胞内活化的影响。 使用质谱细胞仪。本试验的结果将证明CFGR改善疾病反应的疗效 并提供深入了解肥胖诱导的B-ALL化疗耐药性的机制，可能导致 治疗这种致命疾病的模式转变。