Sequestration and deactivation of anthracycline by adipocytes in the leukemia microenvironment

白血病微环境中脂肪细胞对蒽环类药物的封存和失活

基本信息

批准号：
9384148
负责人：
Stan Gee Louie
金额：
$ 38万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9384148
关键词：
Acute Lymphocytic Leukemia Address Adipocytes Adipose tissue Adult Affect Aftercare Age Alpha Cell Anthracyclines Anthraquinones Back Bone Marrow Cell Culture Techniques Cells Cellular Structures Child Childhood Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Data Daunorubicin Development Diagnosis Dose Doxorubicin Drug Kinetics Drug or chemical Tissue Distribution Duborimycin Endocrinology Enzymes Epirubicin Evaluation Exposure to Gender Goals Grant Hematologic Neoplasms Human Idarubicin In Vitro Incidence Individual Knock-out Lead Link Lymphocyte Malignant Childhood Neoplasm Malignant Neoplasms Marrow Measures Mediating Metabolism Mitoxantrone Modeling Monitor Mus Obese Mice Obesity Outcome Overweight Patients Pharmaceutical Preparations Pharmacology Plasma Relapse Risk Sampling Site Solid Testing Thinness Time Treatment Failure Treatment outcome Vincristine asparaginase base cancer cell cancer type chemotherapy clinically relevant cytotoxic experimental study high risk improved in vivo inhibitor/antagonist killings leukemia lipophilicity mortality mouse model multidisciplinary novel obesity in children oncology pharmacokinetic model relapse risk therapy resistant tissue culture

项目摘要

Obesity increases both the incidence and mortality of numerous types of cancer. Children and adults who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to their lean counterparts. Using mouse and tissue culture models, we showed that obesity directly impacts the progression and treatment outcome of ALL. We discovered that adipocytes protect ALL cells from a number of chemotherapies, including the anthracycline daunorubicin (DNR). We have found that fat cells break down DNR to an inactive form, which depletes local levels and protects nearby ALL cells from this chemotherapy. In the present grant, we will further elucidate this mechanism, using a combination of cell culture, mouse experiments, and clinical studies. We will first investigate which enzymes in adipocytes contribute to their ability to breakdown anthracyclines like DNR, and explore strategies to block these enzymes. We will use mouse models to determine how adipocytes in vivo alter systemic DNR availability, as well as that in the bone marrow and other ALL microenvironments. We will also explore how clinical variables such as age and gender alter these effects. Finally, we will perform a limited sampling PK study in lean and obese children, to estimate DNR and DNR-ol plasma and intracellular exposure during ALL therapy. These studies will increase our understanding of how the leukemia microenvironment can contribute to treatment failure, particularly in the obese state. Findings could lead to improved strategies for anthracycline dosing and monitoring in children and adults. These results, along with our previous studies on how adipocytes affect vincristine and L-asparaginase PK and PD, will lay the groundwork for a personalized dosing study of Induction chemotherapies in children with ALL.

肥胖增加了多种类型癌症的发病率和死亡率。儿童和成人在诊断出高风险急性淋巴细胞白血病时肥胖（所有）风险增加了50％与他们的精益相比，复发。使用小鼠和组织培养模型，我们表明肥胖直接影响所有人的进展和治疗结果。我们发现脂肪细胞保护所有来自多种化学疗法的细胞，包括蒽环普氨拟甲蛋白（DNR）。我们找到了脂肪细胞将DNR分解为一种不活跃的形式，该形式耗尽了局部水平并保护附近所有细胞从这种化学疗法中。在目前的赠款中，我们将使用细胞培养的组合进一步阐明这种机制实验和临床研究。我们将首先研究脂肪细胞中哪种酶有助于其能够分解诸如DNR之类的蒽环类动物，并探索阻止这些酶的策略。我们将使用鼠标模型以确定体内脂肪细胞如何改变全身性DNR的可用性，以及骨骼中的脂肪细胞骨髓和其他所有微环境。我们还将探讨年龄和性别等临床变量如何改变这些影响。最后，我们将在精益和肥胖的孩子中进行有限的抽样PK研究，以估计在所有疗法期间，DNR和DNR-OL血浆和细胞内暴露。这些研究将增加我们的了解白血病微环境如何导致治疗失败，特别是在肥胖国家。调查结果可能导致改进儿童邻志剂量和监测的策略成年人。这些结果以及我们先前关于脂肪细胞如何影响长春新碱和L-天冬酰胺酶的研究 PK和PD将为儿童诱导化疗的个性化剂量研究奠定基础所有人。