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

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

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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.

项目摘要/摘要常规处方的镇痛药是Mu-阿片受体（µOR; OPRM1基因）的潜在活化剂，在许多癌症类型中表达，可以影响癌细胞的存活和救生的效率化学疗法。对于癌症患者，OID的使用通常与化学疗法相吻合，使OID- 化学疗法相互作用不可避免。对于某些癌症，包括肺，前列腺，胃，乳房和食管癌，使用OIOID和µOR表达增加与肿瘤生长增加有关转移和较短的患者生存。相反，用于胶质母细胞瘤的体外和动物模型研究，某些乳腺癌以及T-和B细胞急性白血病，阿片类药物刺激癌细胞死亡，在某些情况下，增强细胞毒性化学治疗反应。看似矛盾的影响可能具有浓度 - 依赖性维度作为生理阿片类药物暴露趋于诱导促销作用，而超染色体生理阿片类药物的暴露通常与癌细胞死亡有关。而激活可以增强遗传毒性化疗在急性淋巴细胞白血病中的杀伤作用，我们的初步数据演示阿片类药物拮抗费城染色体阳性（pH+）慢性的凋亡反应髓样白血病细胞（K562）至分子靶向的酪氨酸激酶抑制剂（TKI）化学疗法。作为用遗传毒性和分子靶向化学疗法治疗白血病，以评估临床使用的阿片类药物在白血病细胞中拮抗或协同杀伤是紧迫的医疗需求。我们提出检验中心假设的建议，化学治疗反应将在存在的情况下发生变化三个目的的蛋白类药物的临床相关浓度。特定目标1：量化护理标准白血病患者的卵毒素暴露并确定暴露。假设1：室内变异性由于继承的代谢差异，疾病状况和治疗 - 相关的药代动力学改变。特定目的2：在白血病细胞系中，响应的变化将确定基于白血病亚型和µOR功能的化学疗法。假设2：在临床上 - 经验丰富的卵巢类药物会改变不同白血病亚型的化学治疗反应与µOR功能相对应> 25％。特定目标3：在白血病患者中将确定基于临床和分子因子的化学疗法DDI。假设3：临床和与阿片类化学疗法DDI会议化疗抗性相关的分子特征存在 > 20％的患者处方阿片类药物。了解μor活性对化学治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在OID处方中，潜在的耐药性，救济或无反应和驱动精度药物。这提案将提供关键的初步数据，以支持旨在预测化学治疗改变的NIH R01 由于接受性白血病治疗的患者的支持性护理药物的反应。