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.

摘要： 乳腺癌是北美所有种族妇女最常见的恶性肿瘤， 女性第二大死亡原因（DHHS、CDC和NCI; 2014）以及NIH总体估计成本 2011年，美国的直接医疗费用超过2000亿美元，其中887亿美元。世界卫生组织 预测到2020年，全球癌症病例将增加到1500万新病例。在晚期，骨骼 转移引起失能性疼痛，并且在75-90%的癌症患者中突出。一线治疗 骨癌疼痛包括μ阿片受体激动剂。众所周知，阿片类药物会产生不需要的副作用， 对癌症患者的影响包括严重嗜睡、便秘等，但最近已被证明 （临床和临床前）增加骨丢失和骨折的风险。此外，持续的阿片类药物 证明了包括乳腺癌在内的不同癌症的增殖和迁移有增加的倾向 癌 来自我们实验室和其他实验室的数据表明，大麻素CB 2激动剂可能对 缓解骨癌疼痛和骨质流失。选择性CB 2激动剂显著抑制骨癌疼痛， 不会导致CB 1激动剂或麻醉剂的精神或欣快效应。最近的报告和 来自我们实验室的数据已经确定CB 2激动剂显著减少药物滥用的自我给药 包括可卡因和麻醉剂增加内源性大麻素（MAGL抑制以增加2- 花生四烯基甘油-2AG）可以调节骨质，减少促伤害感受因子并发挥协同作用 与吗啡一起抑制癌症诱导的骨痛（CIBP）并减弱肿瘤增殖。 我们使用小鼠骨癌模型的初步研究表明，MAGL抑制和CB 2 受体活化通过调节NF-κB抑制促炎细胞因子/趋化因子。然而， 已知的内源性CB 2系统在骨癌疼痛/炎症，以及是否激活的 内源性大麻素（eCB）系统，同时给予μ阿片类药物，将显着帮助骨癌患者。 没有研究MAGL抑制剂或CB 2激动剂与μ M的协同组合。 阿片类激动剂对癌症疼痛、骨完整性、肿瘤增殖或减弱μ阿片类不需要的副作用 方面的影响.我们在表征骨癌疼痛方面的进展导致了12个直接的同行评审 出版物和初步数据，以进一步支持骨中MAGL抑制、CB 2受体活化的研究 癌症疼痛。我们的初步数据表明：1）一个可重复的同基因乳腺癌诱导的骨癌 2）MAG脂肪酶抑制导致2AG显著增加， 减弱癌症引起的疼痛，3）减弱骨丢失的外源性和内源性CB 2激动剂，4） 持续的吗啡单独增加骨降解和细胞因子，5）CB 2激动剂和MAGL抑制剂 减少NF-kB信号传导，抑制几种促炎细胞因子/趋化因子，同时恢复 乳腺癌细胞凋亡，6）CIBP与吗啡和CB 2激动剂的协同抑制，和7）CB 2 无不良副作用的激动剂。因此，MAGLipase抑制剂与吗啡的组合可以是 在缓解骨癌疼痛、抑制乳腺癌增殖同时保持骨量方面具有协同作用。 为了响应最近呼吁提出的题为“开发治疗药物”的提案（RFA PA-15-188）， 内源性大麻素系统治疗疼痛的潜力”和我们的初步发现使我们 假设MAG脂肪酶抑制和/或CB 2受体活化与Mu阿片样物质组合 激动剂将导致在乳房诱导的小鼠模型中疼痛行为的协同抑制。 骨癌疼痛，同时减少阿片类药物引起的骨丢失。机械上，2AG和CB 2 激动剂通过CB 2受体作用，抑制常见的转录因子NF-κB， 细胞因子/趋化因子。我们建议使用行为、生化、免疫和分子策略， 测试在吗啡的存在下（标准临床护理）MAGL抑制和/或CB 2激动剂是否将是一种有效的治疗方法。 乳腺癌引起的骨癌疼痛的有益治疗。这一假设将通过以下目标进行检验 使用我们的CIBP的同基因（非免疫受损）鼠模型： 目标1.确定MAG脂肪酶的抑制是否减轻乳腺癌诱导的骨痛和/或 改变骨吸收和重塑。 目标二。探索MAGLipase抑制和CB 2受体激活是否减弱乳腺癌诱导的 通过共同的转录因子抑制原伤害感受性细胞因子/趋化因子来治疗骨痛。 目标3。确定MAGL抑制剂和CB 2和Mu阿片受体的激活是否导致 协同抑制乳腺癌引起的骨痛，同时减少骨丢失。 这些研究将导致迫切需要的新治疗方法，并可能适用于其他转移性癌症， 包括肺和前列腺。