Opioid-induced changes to chemotherapeutic activity in blood cancer

阿片类药物引起的血癌化疗活性变化

基本信息

批准号：
10674695
负责人：
JONATHAN ERIC CONSTANCE
金额：
$ 20.15万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674695
关键词：
Absence of pain sensation Acute Lymphocytic Leukemia Affect Age Years Animal Model Apoptotic B-Lymphocytes Binding Cell Death Cell Line Cell Separation Cell Survival Central Nervous System Cessation of life Chemoresistance Chemotherapy-Oncologic Procedure Child Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Data Diagnosis Dimensions Disease Drug Interactions Drug Kinetics Drug resistance Enrollment Ensure Fentanyl Flow Cytometry Frequencies Genes Glioblastoma Goals Hematopoietic Neoplasms Image Immunophenotyping In Vitro K-562 Knock-out Leukemic Cell Life Link Literature Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Medical Metabolic Molecular Molecular Target Morphine Neoplasm Metastasis Newly Diagnosed Opioid Opioid Analgesics Outcome Oxycodone Pathway interactions Patients Pharmaceutical Preparations Philadelphia Chromosome Positive Chronic Myelogenous Leukemia Physiological Plasma Population Proliferating Public Health Recurrent disease Relapse Research Proposals Resistance Risk Role Sampling Signal Pathway Signal Transduction Study models Supportive care T-Lymphocyte Testing Therapeutic Therapeutic Effect Treatment Efficacy Treatment Failure Tyrosine Kinase Inhibitor United States National Institutes of Health acute leukemia cell biobank cancer cell cancer diagnosis cancer therapy cancer type cell killing cell type chemotherapy chronic myeloid leukemia cell clinically relevant cytotoxic early experience experience genetic approach genotoxicity high throughput screening insight interpatient variability leukemia leukemia treatment malignant breast neoplasm malignant stomach neoplasm mu opioid receptors opioid exposure opioid use peripheral blood personalized medicine pharmacologic precision medicine prescription opioid prospective response standard of care synergism treatment response treatment risk tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT Routinely prescribed analgesic opioids are potent activators of the mu-opioid receptor (µOR; OPRM1 gene), expressed in many cancer types, and can impact cancer cell survival and the efficacy of lifesaving chemotherapy. For patients with cancer, opioid use often coincides with chemotherapy, making opioid- chemotherapy interactions inevitable. For some cancers, including lung, prostate, gastric, breast, and esophageal cancers, opioid use and increased µOR expression are linked to increased tumor growth, metastases, and shorter patient survival. In contrast, in vitro and animal model studies for glioblastoma, certain breast cancers, and T- and B-cell acute leukemias, opioids stimulate cancer cell death and, in some cases, enhance cytotoxic chemotherapeutic response. The seemingly paradoxical effects likely have a concentration- dependent dimension as physiologic opioid exposures have tended to induce pro-proliferative effects while supraphysiologic opioid exposures are typically associated with cancer cell death. While µOR activation can enhance the killing effect of genotoxic chemotherapy in acute lymphoblastic leukemia, our preliminary data demonstrate opioids antagonize the apoptotic response of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells (K562) to molecularly-targeted tyrosine kinase inhibitor (TKI) chemotherapy. As leukemias are treated with both genotoxic and molecularly targeted chemotherapy assessing the potential for clinically used opioids to antagonize or synergize in leukemic cell killing is an urgent medical need. We propose to test the central hypothesis, that chemotherapeutic response will change in the presence of clinically relevant concentrations of opioids, in three Aims. Specific Aim 1: Quantify standard-of-care opioid exposures and determinants of exposure in patients with leukemia. Hypothesis 1: Interpatient variability in opioid exposure will exceed 50% due to inherent metabolic differences, disease status, and treatment- related pharmacokinetic alterations. Specific Aim 2: In leukemic cell lines, changes in response to chemotherapy based on leukemic subtype and µOR function will be determined. Hypothesis 2: Clinically- experienced concentrations of opioids will change chemotherapeutic response in different leukemic subtypes corresponding with µOR function by >25%. Specific Aim 3: In patients with leukemia, the frequency of opioid- chemotherapy DDIs based on clinical and molecular factors will be determined. Hypothesis 3: Clinical and molecular features associated with opioid-chemotherapy DDI conferring chemotherapy resistance are present in >20% of patients prescribed opioids. Understanding the impact of µOR activity on chemotherapeutic response across similar but biologically distinct leukemia cell types will provide new insights into mechanisms underlying drug resistance, relapse, or non-response and drive precision medicine in opioid prescribing. This proposal will provide key preliminary data to support an NIH R01 aimed at predicting altered chemotherapeutic response due to supportive care medication exposure among patients undergoing treatment for leukemia.

项目概要/摘要常规处方镇痛阿片类药物是 mu-阿片受体（μOR；OPRM1 基因）的有效激活剂，在许多癌症类型中表达，并且可以影响癌细胞的存活和挽救生命的功效对于癌症患者，阿片类药物的使用通常与化疗同时进行，这使得阿片类药物- 对于某些癌症，包括肺癌、前列腺癌、胃癌、乳腺癌和癌症，化疗相互作用是不可避免的。食道癌、阿片类药物的使用和 µOR 表达增加与肿瘤生长增加有关，相比之下，胶质母细胞瘤的体外和动物模型研究表明，转移和患者生存期较短。乳腺癌、T 细胞和 B 细胞急性白血病、阿片类药物会刺激癌细胞死亡，在某些情况下，增强细胞毒性化疗反应。看似矛盾的效果可能有一个浓度- 依赖维度，因为生理性阿片类药物暴露往往会诱发促增殖作用，而超生理性阿片类药物暴露通常与癌细胞死亡有关，而 µOR 激活则可以。增强基因毒性化疗对急性淋巴细胞白血病的杀伤作用，我们的初步数据证明阿片类药物可以拮抗费城染色体阳性 (Ph+) 慢性细胞的凋亡反应骨髓性白血病细胞（K562）与分子靶向酪氨酸激酶抑制剂（TKI）化疗。白血病采用基因毒性和分子靶向化疗来治疗，评估治疗的潜力临床上使用阿片类药物来拮抗或协同杀伤白血病细胞是我们迫切的医疗需求。提议检验中心假设，即化疗反应会在存在的情况下发生变化阿片类药物的临床相关浓度，三个具体目标 1：量化护理标准。白血病患者的阿片类药物暴露和暴露的决定因素假设 1：患者间差异。由于固有的代谢差异、疾病状态和治疗，阿片类药物暴露量将超过 50% 相关的药代动力学改变。具体目标 2：在白血病细胞系中，响应的变化。将根据白血病亚型和 µOR 功能确定化疗方案假设 2：临床-。阿片类药物的浓度会改变不同白血病亚型的化疗反应与 µOR 函数对应 >25% 具体目标 3：在白血病患者中，阿片类药物的使用频率化疗 DDI 将根据临床和分子因素确定。假设 3：临床和分子因素。存在与阿片类化疗 DDI 相关的分子特征，赋予化疗耐药性 >20% 的患者服用阿片类药物，了解 µOR 活性对化疗的影响。相似但生物学上不同的白血病细胞类型的反应将为机制提供新的见解潜在的耐药性、复发或无反应，并推动阿片类药物处方的精准医学。该提案将提供关键的初步数据来支持 NIH R01，旨在预测化疗药物的改变接受白血病治疗的患者因支持性护理药物暴露而产生的反应。