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...