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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.

项目总结/文摘