Role of beta-endorphin in cancer therapy induced fatigue

描述（由申请人提供）：在接受放射或化疗的癌症患者中，高达80%的患者会出现疲劳，并且明显使人衰弱。我们的实验室研究介导紫外线诱导色素沉着的皮肤信号。紫外线破坏角化细胞中的DNA，从而稳定p53，刺激促阿皮黑色素皮质素（POMC）的表达。接着，POMC被切割成几种多肽，其中一种是促黑素细胞激素，可以激活色素沉着。另一种源自POMC的肽是2-内啡肽。我们观察到在重复低剂量紫外线照射后，全身血液中2-内啡肽水平升高。多项研究表明，紫外线可能引发鸦片样成瘾行为，这可能是由UV- pomc -2内啡肽轴介导的。我们认为，这种行为联系的起源可能与寻求阳光的行为的进化优势有关，以维持紫外线衍生的皮肤维生素D合成。由于这一途径是由p53 （DNA损伤传感器）控制的，我们测试了非紫外线DNA损伤触发因素，特别是电离辐射或某些化疗药物，是否也可能触发2-内啡肽合成，结果发现确实如此。疲劳是一种突出的阿片类药物表型，并且伴随大多数癌症患者接受已知可有效诱导p53的治疗。在啮齿类动物中，我们观察到大剂量单次或重复分次剂量的紫外线或电离辐射以及阿霉素后血液中2-内啡肽的升高。与晒黑/色素沉着一样，这种2-内啡肽反应在p53-/-小鼠中不存在。采用分段尾电离照射（模拟癌症放射治疗），我们观察到几周后血液中2-内啡肽的升高。定量大鼠活动测量显示严重的运动抑制，表明严重的疲劳，这与2-内啡肽的血液升高在时间上精确相关。最重要的是，用5-阿片受体拮抗剂纳洛酮治疗后，运动/疲劳变化迅速而完全逆转。2-内啡肽在人体辐射疲劳中的作用尤其重要，因为调节这一途径的药物很容易应用于患者。我们建议将这些临床前和临床研究扩展到以下具体目标：1)开展一项前瞻性临床试验，在接受乳腺癌化疗和/或放疗的人群中检测血液2-内啡肽水平、疲劳自我评估和其他阿片相关行为表型；2)在临床前剖析该途径的参数，具体测试a)辐射剂量反应，b)疲劳与辐射皮肤毒性之间的关系，c)电子束辐射，d)；阿霉素引起的疲劳（纳洛酮可逆性），e)维生素D缺乏的串扰/影响，f)纳曲酮计划/剂量的优化。这些基于机制的研究可能为使用现有药物快速应用阿片通路调节奠定基础，作为针对癌症患者这一主要生活质量挑战的靶向治疗方法。

DESCRIPTION (provided by applicant): Fatigue occurs in up to 80% of cancer patients undergoing radiation or chemotherapy and is significantly debilitating. Our lab studies skin signaling which mediates UV induced pigmentation. UV damages DNA in keratinocytes, thereby stabilizing p53 which stimulates expression of pro-opiomelanocortin (POMC). In turn, POMC is cleaved into several peptides, one of which, Melanocyte Stimulating Hormone, activates pigmentation. Another POMC derived peptide is 2-endorphin. We have observed elevations in systemic blood levels of 2-endorphin following repeated low-dose UV radiation. Multiple studies suggest that UV may trigger opiate-like addictive behaviors, which are likely mediated by this UV-POMC-2endorphin axis. We believe the origins of this behavioral linkage may relate to evolutionary advantages of sun-seeking behaviors to maintain UV derived cutaneous vitamin D synthesis. Since control of this pathway is exerted by p53 (DNA damage sensor), we tested whether non-UV DNA damage triggers, especially ionizing radiation or certain chemotherapeutics, may also trigger 2-endorphin synthesis and found that they do. Fatigue is a prominent opiate phenotype, and one which accompanies the majority of cancer patients undergoing therapies which are known to potently induce p53. We observed elevations in blood 2-endorphin following either large single doses or repeated fractionated doses of either UV or ionizing radiation, as well as adriamycin in rodents. As with tanning/pigmentation, this 2-endorphin response is absent in p53-/- mice. Using fractionated tail ionizing irradiation (simulating cancer radiation therapy) we observed elevations in blood 2-endorphin after several weeks. Quantitative rat actimetry measurements revealed major locomotor depression, indicative of severe fatigue, which precisely correlated temporally with 2-endorphin blood elevations. Most importantly, the locomotor/fatigue changes were rapidly and fully reversed by treatment with the 5-opiate receptor antagonist naloxone. A role for 2-endorphin in human radiation fatigue would be particularly important because drugs which modulate this pathway are readily available to apply to patients. We propose to expand these studies preclinically and clinically in the following Specific Aims: 1) carry out a prospective clinical trial to examine blood 2-endorphin levels together with self-assessments of fatigue and other opiate-related behavioral phenotypes using validated questionnaire instruments in humans undergoing chemotherapy and/or radiation therapy for breast cancer, 2) dissect parameters of this pathway pre-clinically, specifically testing a) radiation dose-response, b) relationship between fatigue and radiation skin toxicity, c) electron beam radiation, d), adriamycin induced fatigue (naloxone reversibility), e) crosstalk/impact of vitamin D deficiency, and f) optimization of naltrexone schedule/dosing. These mechanism-based studies may set the stage for rapid application of opiate pathway modulation using existing drugs, as a targeted therapeutic approach for this major quality of life challenge in cancer patients.