Opioid-induced changes to chemotherapeutic activity in blood cancer

项目摘要/摘要 常规处方的止痛阿片类药物是u-阿片受体(µOR；OPRM1基因)的有效激活剂， 在许多癌症类型中表达，并可影响癌细胞存活和挽救生命的疗效 化疗。对于癌症患者，阿片类药物的使用通常与化疗同时进行，使阿片类药物- 化疗的相互作用是不可避免的。对于一些癌症，包括肺癌、前列腺癌、胃癌、乳腺癌和 食道癌、阿片类药物的使用和uOR表达增加与肿瘤生长增加有关， 转移，以及较短的患者生存期。相比之下，对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。看似自相矛盾的影响可能集中在-- 依赖维度，因为生理性阿片类药物暴露倾向于诱导促增殖效应，而 超生理阿片类药物暴露通常与癌细胞死亡有关。而微或激活可以 增强基因毒性化疗对急性淋巴细胞白血病杀伤作用的初步研究 阿片类药物拮抗Ph+慢性Ph阳性患者的细胞凋亡反应 髓系白血病细胞(K562)分子靶向酪氨酸激酶抑制剂(TKI)化疗。AS 白血病的治疗既有基因毒性的，也有分子靶向的，评估了 临床上使用阿片类药物来拮抗或协同杀伤白血病细胞是医学上的迫切需要。我们 建议检验中心假设，即化疗反应会在存在的情况下发生变化 临床上相关的阿片类药物浓度，有三个目的。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决定因素。假设1：患者间的变异性 由于固有的代谢差异、疾病状况和治疗，阿片类药物暴露的比例将超过50%- 相关的药代动力学改变。特定目标2：在白血病细胞系中，对 将根据白血病亚型和µOR功能确定化疗方案。假设2：临床上- 阿片类药物的经验浓度将改变不同白血病亚型的化疗反应 与µOR函数对应&gt；25%。具体目标3：在白血病患者中，阿片类药物的频率- 将根据临床和分子因素确定化疗DDIS。假设3：临床和 阿片类药物化疗DDI导致化疗耐药的分子特征 20%的患者使用阿片类药物。了解uOR活性对化疗的影响 跨越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中的精准药物。这 该提案将提供关键的初步数据，以支持旨在预测化疗变化的NIH R01 正在接受白血病治疗的患者中支持性护理药物暴露的反应。

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.