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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

基本信息

批准号：
7884774
负责人：
TODD W VANDERAH
金额：
$ 31.11万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884774
关键词：
AM 1241 Absence of pain sensation Address Adverse effects Agonist American Cancer Society Analgesics Animals Attenuated Behavior Behavioral Biochemical Bone Density Bone Pain Bone Resorption Bone remodeling Breast Breast Cancer Cell Breast Cancer Treatment CNR2 gene Calcium Cancer Model Cancer Patient Cancer cell line Cannabinoids Cell Proliferation Cells Characteristics Chronic Clinical Research Constipation Data Deterioration Development Diagnosis Disease Dose Drowsiness Endocannabinoids Equilibrium Female Femur Fracture Green Fluorescent Proteins Growth Health Care Costs Human Hypersensitivity Image Immune Immunocompromised Host In Vitro Inflammatory Innovative Therapy Interleukin-12 Interleukin-6 Label Laboratories Malignant Bone Neoplasm Malignant Neoplasms Marrow Measures Mechanics Mediating Medical Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Breast Modeling Modification Molecular Morphine Morphine Users Motor Activity Mus Neoplasm Metastasis Neuraxis Neurons Neuropathy North America Opioid Osteoblasts Osteoclasts Osteoporosis Pain Patients Proliferating Quality of life Receptor Activation Reporting Rewards Risk Rodent Role Sagittaria Sedation procedure Serum Staging Stimulus Structure Symptoms System Testing Therapeutic Uses Thick Time United States National Institutes of Health Ventilatory Depression Woman addiction attenuation bone bone mass cancer pain chronic pain cost cytokine design fitness functional status improved in vivo inflammatory neuropathic pain inflammatory pain interest malignant breast neoplasm mouse model mu opioid receptors neoplastic cell novel novel therapeutic intervention osteogenic osteoprogenitor cell pain behavior pain inhibition pre-clinical preference prevent public health relevance research study response spontaneous pain statistics tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Statistics show that 1 out of every 7 females in the US will develop breast cancer in their lifetime, with 75-95% of patients with advanced breast cancer having chronic, excruciating pain associated with metastasis of the cancer to bone. Pain from metastatic breast cancer appears to be simultaneously driven by inflammatory, neuropathic and tumorigenic mechanisms. Such pain is extremely difficult to treat causing quality of life in these patients to be severely compromised. Being able to more fully control bone cancer pain, without the side effects of currently available analgesics, would significantly improve the functional status, quality of life while reducing health care costs in breast cancer patients with skeletal metastases. A major problem in designing new therapies to treat breast cancer-induced bone pain has been the lack of a model available to define the mechanisms that generate and maintain breast cancer induced bone pain. The major thrust of this proposal is to use a mouse model we have recently developed that closely mirrors the bone remodeling and chronic pain often observed in patients with breast cancer- induced bone pain. Mouse 66.1 breast cancer cells, stably transfected with green fluorescent protein, are injected and confined to the intramedullary space of the femur of the non-immunocompromised mice. Over a twenty-one day period, these tumor cells proliferate in the marrow space and induce bone remodeling, bone cancer related pain behaviors and ultimately fracture of the bone. Recent data has suggested that cannabinoid CB2 agonists can provide significant analgesia in a variety of preclinical pain models with a minimal side effect profile. Intriguingly, data from osteoporosis studies have suggested that activation of CB2 receptors is pro-osteogenic (bone-building) and preliminary data from our lab suggests CB2 agonists have direct anti-tumor effects in both mouse and human breast cancer cells. In the present proposal, we will explore the hypothesis that CB2 agonists can have multiple beneficial actions to reduce breast cancer-induced bone pain, reduce tumor induced bone destruction and fracture and reduce the growth of breast cancer cells both in vitro and in vivo. The specific hypotheses to be tested are: CB2 receptor activation will result in antihypersensitivity in a murine model of breast-induced bone cancer pain while lacking the unwanted side effects seen with current analgesic therapies. Experimental studies proposed in this application will: 1) aid in our understanding of the pain relieving effects of the CB2 receptors in breast-induced bone cancer, 2) identify whether CB2 agonists will enhance bone remodeling and reduce bone fracture in a murine model of bone cancer using breast cancer cells, 3) identify whether CB2 agonists inhibit the proliferation of breast cancer cells both in vitro and in vivo, 4) identify whether CB2 receptor activation results in a decrease in pronociceptive factors including IL-12, IL-6, and TNF1, 5) identify whether chronic administration of CB2 agonists in a murine model of bone cancer results in unwanted side effects, and 6) most importantly, offer a novel target for new and innovative therapy for patients suffering from bone cancer due to breast metastases. New treatments are urgently needed that would result in adequate pain relief without the debilitating CNS side effects of current agents, as well as inhibit bone degradation, avoiding painful bone fractures induced by the metastases and result in disease modification. These studies are likely to offer new opportunities for the development of strategies to treat pain resulting from metastasis of breast to bone as well as possible applications to other bone cancers. PUBLIC HEALTH RELEVANCE: Breast cancer is the most frequent malignant tumor in women in North America. With nearly 200,000 women diagnosed each year in the U.S., there is a great need for novel therapeutic intervention in treating breast cancer patients in pain. Breast cancer commonly metastasizes to the bone resulting in excruciating pain, bone remodeling and eventual bone fracture contributing to incapacitating pain and limited or total loss of mobility. The U.S. National Institutes of Health estimate overall costs of cancer in the U.S. in 2006 to be $206.3 billion with $78.2 billion in direct medical costs (Arrowhead Publishers, 2008). Unfortunately, current therapies result in unwanted side effects and even promote further deterioration of the bone and hypersensitivities. This proposal addresses whether CB2 agonist will attenuate breast cancer-induced bone pain without resulting in unwanted side effects seen with current analgesic therapies. CB2 receptors are found on immune cells and on cells that regulate bone mass but not on neurons of the central nervous system. The activation of CB2 receptors with agonists inhibits several inflammatory factors that promote pain, significantly attenuate spontaneous pain due to bone cancer, inhibit the degradation of bone, and reduce breast cancer cell proliferation within the bone. Yet, CB2 agonists do not result in the unwanted side effects such as constipation, somnolence, respiratory depression, analgesic tolerance or rewarding "addiction" effects.

描述（由申请人提供）：统计数据显示，美国每7名女性中就有1名会在其一生中患上乳腺癌，75-95%的晚期乳腺癌患者患有慢性、剧烈的疼痛，并伴有癌症向骨骼的转移。转移性乳腺癌引起的疼痛似乎同时受到炎症、神经性和致瘤机制的驱动。这种疼痛极难治疗，导致这些患者的生活质量严重受损。如果能够更全面地控制骨癌疼痛，而没有现有镇痛药的副作用，将显著改善骨骼转移的乳腺癌患者的功能状态和生活质量，同时降低医疗保健费用。设计治疗乳腺癌引起的骨痛的新疗法的一个主要问题是缺乏一个可用的模型来定义产生和维持乳腺癌引起的骨痛的机制。这项提议的主要目的是使用我们最近开发的一种小鼠模型，该模型密切反映了在乳腺癌引起的骨痛患者中经常观察到的骨重塑和慢性疼痛。小鼠66.1乳腺癌细胞，稳定转染绿色荧光蛋白，注射并限制在非免疫受损小鼠股骨的髓内间隙。在21天的时间里，这些肿瘤细胞在骨髓空间增殖，诱导骨重塑，骨癌相关的疼痛行为，最终导致骨骨折。最近的数据表明，大麻素CB2激动剂可以在各种临床前疼痛模型中提供显著的镇痛作用，且副作用最小。有趣的是，来自骨质疏松研究的数据表明，CB2受体的激活有利于成骨（骨建设），我们实验室的初步数据表明，CB2激动剂对小鼠和人类乳腺癌细胞都有直接的抗肿瘤作用。在本提案中，我们将探讨CB2激动剂在体外和体内可具有多种有益作用的假设，以减少乳腺癌诱导的骨痛，减少肿瘤诱导的骨破坏和骨折，并减少乳腺癌细胞的生长。需要验证的具体假设是：CB2受体激活将导致乳腺诱导骨癌疼痛小鼠模型的抗超敏反应，同时缺乏当前镇痛疗法所见的不良副作用。本申请所提出的实验研究将：1)帮助我们了解CB2受体在乳腺诱导的骨癌中的镇痛作用，2)在使用乳腺癌细胞的小鼠骨癌模型中，确定CB2激动剂是否会增强骨重塑和减少骨折，3)确定CB2激动剂是否在体外和体内抑制乳腺癌细胞的增殖，4)确定CB2受体激活是否导致包括IL-12， IL-6和TNF1在内的前感觉因子的降低。5)在小鼠骨癌模型中确定慢性给药CB2激动剂是否会导致不良副作用，6)最重要的是，为乳腺癌转移性骨癌患者提供新的创新治疗靶点。迫切需要新的治疗方法，既能充分缓解疼痛，又不会像目前的药物那样对中枢神经系统产生衰弱性副作用，同时又能抑制骨降解，避免因转移引起的疼痛性骨折，并导致疾病的改变。这些研究可能为开发治疗乳腺癌骨转移引起的疼痛的策略以及可能应用于其他骨癌提供新的机会。