Cannabinoid CB2 Agonists for Treatment of Breast Cancer Induced Bone Pain

大麻素 CB2 激动剂用于治疗乳腺癌引起的骨痛

• 批准号: 9329913
• 负责人: TODD W VANDERAH
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329913
• 关键词: 2-arachidonylglycerol; Address; Adverse effects; Agonist; Animals; Apoptosis; Attenuated; Behavioral; Biochemical; Bone Pain; Bone Resorption; Bone neoplasms; Bone remodeling; Bone structure; Breast; Breast Cancer Cell; Breast Cancer Treatment; CNR1 gene; CNR2 gene; Cancer Model; Cancer Patient; Cannabinoids; Cause of Death; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Cocaine; Combined Modality Therapy; Constipation; Data; Death Rate; Disseminated Malignant Neoplasm; Drowsiness; Eicosanoids; Endocannabinoids; Fracture; Human; Hypersensitivity; Immune; Inflammation; Inflammatory; Laboratories; Lung; Malignant Bone Neoplasm; Malignant Neoplasms; Measures; Mechanics; Medical; Metastatic Neoplasm to the Bone; Molecular; Morphine; Mus; NF-kappa B; Narcotics; Nociception; North America; Opiates; Opioid; Osteogenesis; Pain; Pain management; Patients; Peer Review; Preparation; Prostaglandins; Prostate; Publications; Quality of life; Race; Receptor Activation; Reporting; Reproducibility; Risk; Rodent; Self Administration; Signal Transduction; Stat5 protein; System; Testing; Therapeutic; Time; Transcriptional Regulation; Tumor Burden; United States National Institutes of Health; Woman; World Health Organization; bisphosphonate; bone; bone loss; bone mass; cancer pain; chemokine; clinical care; cost; cytokine; drug of abuse; endogenous cannabinoid system; inhibitor/antagonist; malignant breast neoplasm; migration; mouse model; mu opioid receptors; osteoprogenitor cell; pain behavior; pain inhibition; pre-clinical; response; synergism; transcription factor; tumor; tumor microenvironment

Abstract: Breast cancer is the most frequent malignant tumor of women of all races in North America and is the second leading cause of death among women (DHHS, CDC, & NCI; 2014) with an overall NIH estimate costs to the U.S. over $200 billion with $88.7 billion in direct medical costs in 2011. The World Health Organization predicts that global cases of cancer will rise to 15 million new cases by 2020. In advanced stages, skeletal metastasis causes incapacitating pain and is prominent in 75–90% of cancer patients. First line therapy to treat bone cancer pain includes mu opioid receptor agonists. Opioids are well known for producing unwanted side effects in cancer patients including severe somnolence, constipation, etc. but recently have been shown (clinical and preclinical) to enhance the risk of bone loss and fracture. In addition, sustained opioids have demonstrated a propensity for increasing proliferation and migration of different cancers including breast cancer. Data from our laboratory, and others, suggest that cannabinoid CB2 agonists may be effective in alleviating bone cancer pain and bone loss. Selective CB2 agonists significantly inhibit bone cancer pain while NOT resulting in the psychotropic or euphoric effects seen with CB1 agonists or narcotics. Recent reports and data from our lab have identified CB2 agonists as significantly reducing self-administration of drugs of abuse including cocaine and narcotics. Increasing endogenous cannabinoids (MAGL inhibition to increase 2- arachidonylglycerol - 2AG) may regulate bone mass, decrease pro-nociceptive factors and act synergistically with morphine to inhibit cancer-induced bone pain (CIBP) and attenuate tumor proliferation. Our preliminary studies using a murine bone cancer model indicate that MAGL inhibition and CB2 receptor activation inhibits proinflammatory cytokines/chemokines via regulating NF-κB. Yet, there is very little known about the endogenous CB2 system in bone cancer pain/inflammation, and whether the activation of the endocannabinoid (eCB) system, while administering mu opioids, will significantly aid bone cancer patients. There are NO studies investigating the synergistic combination of MAGL inhibitor or CB2 agonists with a mu opioid agonist on cancer pain, bone integrity, tumor proliferation, or attenuating mu opioid unwanted side effects. Our progress in characterizing bone cancer pain has resulted in twelve direct peer-reviewed publications and preliminary data to further support studies of MAGL inhibition, CB2 receptor activation in bone cancer pain. Our preliminary data demonstrate; 1) a reproducible syngeneic breast-induced bone cancer model representative of the clinical state, 2) MAGLipase inhibition resulting in increased 2AG, significantly attenuating cancer-induced pain, 3) exogenous and endogenous CB2 agonists attenuating bone loss, 4) sustained morphine alone increases bone degradation and cytokines, 5) CB2 agonists and MAGL inhibitors decrease NF-kB signaling, inhibiting several pro-inflammatory cytokines/chemokines, while reinstating apoptosis in breast cancer cells, 6) synergistic inhibition of CIBP with morphine and CB2 agonists, and 7) CB2 agonists lacking unwanted side effects. Hence, MAGLipase inhibitors in combination with morphine may be synergistic in alleviating bone cancer pain, attenuate breast cancer proliferation while maintaining bone mass. In response to the recent call for proposals (RFA PA-15-188) titled “Developing the Therapeutic Potential of the Endocannabinoid System for Pain Treatment” and our preliminary findings have led us to hypothesize that MAGLipase inhibition and/or CB2 receptor activation, in combination with a Mu opioid agonist will result in the synergistic inhibition of pain behaviors in a murine model of breast-induced bone cancer pain while attenuating bone loss seen with opioids. Mechanistically, 2AG and CB2 agonists act via the CB2 receptor to inhibit a common transcription factor, NF-κB, regulating multiple cytokines/chemokines. We propose to use behavioral, biochemical, immune and molecular strategies to test whether MAGL inhibition and/or CB2 agonist, in the presence of morphine (standard clinical care) will be a beneficial therapy for breast-induced bone cancer pain. This hypothesis will be tested by the following Aims using our syngeneic (non-immune-compromised) murine model of CIBP: Aim 1. Determine whether the inhibition of MAGLipase attenuates breast cancer-induced bone pain and/or alter bone resorption and remodeling. Aim 2. Explore whether MAGLipase inhibition and CB2 receptor activation attenuates breast cancer-induced bone pain by inhibiting pronociceptive cytokines/chemokines via a common transcription factor. Aim 3. Determine whether a MAGL inhibitor and the activation of the CB2 and Mu opioid receptors result in the synergistic inhibition of breast cancer-induced bone pain while reducing bone loss. These studies will lead to urgently needed new treatments and may likely apply to other metastatic cancers, including lung and prostate.

抽象的： 乳腺癌是北美所有种族中最常见的女性恶性肿瘤，是 妇女中的第二大死亡原因（DHHS，CDC和NCI; 2014）总体NIH估算成本 2011年，美国超过2000亿美元，直接医疗费用为887亿美元。世界卫生组织 预测，到2020 转移引起的导致疼痛无能产生疼痛，在75-90％的癌症患者中突出。 骨癌疼痛包括阿片类药物受体激动剂。 在癌症患者中的影响，无法严重，建筑等。 （临床和临床前）为增强骨质流失和断裂的风险。 证明了增加包括乳房在内的不同癌症的繁殖和迁移的倾向 癌症。 我们实验室和其他的数据表明，大麻素CB2激动剂可能有效 减轻骨癌疼痛和骨质流失。 没有产生CB1激动剂或麻醉品的精神效果 我们实验室的数据确定CB2激动剂大大降低了滥用药物的自我管理 包括可卡因和麻醉品。 Arachidonylglycerol -2Ag）可能会定期骨骼，减少pro -noctatee因子并协同起作用 将吗啡用于吸入癌症引起的骨痛（CIBP）并减轻肿瘤刺激。 我们使用鼠骨癌模型模型的初步研究指示MAGL抑制和CB2 受体激活通过调节NF-κB抑制促炎细胞因子/趋化因子。 关于骨癌疼痛/炎症中内源性CB2系统的了解，以及是否激活 内源性大麻素（欧洲央行）系统虽然递给阿片类药物，但将显着有助于骨癌患者。 尚无研究调查MAGL抑制剂或CB2激动剂与MU的协同组合 阿片类药物激动剂在癌症疼痛，骨骼完整性，肿瘤增殖或衰减MU阿片类药物不需要的一面 效果我们在骨癌疼痛的表征上导致了十二个直接同行评审 出版物和初步数据，以进一步支持MAGL不可自然的研究，CB2受体激活骨骼 癌症疼痛。 代表临床状态的模型，2）遗传的maglipase遗传导致2ag的增加，显着增加 减弱癌症的疼痛，3）外源性和内源性CB2激动剂减弱骨质流失，4） 单独的吗啡会增加骨骼降解和细胞因子，5）CB2激动剂和MAGL抑制剂 DEREESE NF-KB信号传导，遗传了几种促炎细胞因子/趋化因子，同时还原 乳腺癌细胞的凋亡，6）与吗啡和CB2激动剂的CIBP协同作用，以及7）CB2 激动剂缺乏不必要的副作用。 减轻骨癌疼痛的协同作用 为了回应最近提出的提案（RFA PA-15-188），标题为“开发治疗性 内源性大麻素系统用于疼痛治疗的潜力”，我们的预后结果使我们得以实现 假设Maglipase的不可自然和/或CB2受体激活与MU阿片类药物结合 激动剂将导致乳房诱导的鼠模型中的协同抑制剂 骨癌疼痛，同时衰减阿片类药物的骨骼损失。 激动剂通过CB2受体起作用，以继承常见的转录因子NF-κB，调节多个 细胞因子/趋化因子。 测试MAGL抑制和/或CB2激动剂是否存在吗啡（标准临床护理）将是一个 乳房诱发的骨癌疼痛的有益疗法将通过以下AMS检验 使用我们的cibp的同性（非免疫功能低下的）鼠模型： 目标1。确定遗传酶是否减轻了癌症引起的骨痛和/或 改变骨骼度假胜地和重塑。 AIM 2。探索MARPLIPASE抑制和CB2受体激活是否会减弱乳腺癌诱导的 骨痛通过抑制普通转录因子抑制造影性细胞因子/趋化因子。 AIM 3。确定MAGL抑制剂和CB2 andooid受体的激活是否会导致您 对乳腺癌引起的骨痛的协同抑制，同时减少骨骨质流失。 这些研究将导致迫切需要新的治疗方法，并且可能会导致其他Metatatatatices， 包括肺和前列腺。