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）：统计数据表明，美国每7名女性中有1名将在其一生中患上乳腺癌，其中75-95％的晚期乳腺癌患者患有慢性，令人难以置信的疼痛，这与癌症的转移有关。转移性乳腺癌的疼痛似乎同时受到炎症，神经性和肿瘤性机制的驱动。这种疼痛极难治疗这些患者的生活质量严重损害。能够更全面地控制骨癌疼痛，而没有当前可用的镇痛药的副作用，将显着改善功能状况，生活质量，同时降低骨骼转移患者的医疗保健成本。设计新疗法以治疗乳腺癌引起的骨痛的一个主要问题是缺乏可用的模型来定义产生和维持乳腺癌引起的骨痛的机制。该提案的主要目的是使用我们最近开发的小鼠模型，与乳腺癌诱发的骨痛患者经常观察到骨骼重塑和慢性疼痛。小鼠66.1用绿色荧光蛋白稳定转染的乳腺癌细胞被注射，并局限于非免疫力低下的小鼠股骨的髓内空间。在二十一日的时间内，这些肿瘤细胞在骨髓空间中扩散，并诱导骨骼重塑，骨癌相关的疼痛行为以及最终的骨骼骨折。最近的数据表明，大麻素CB2激动剂可以在各种具有最小副作用曲线的临床前疼痛模型中提供明显的镇痛作用。有趣的是，来自骨质疏松研究的数据表明，CB2受体的激活是促骨（骨建造），而我们实验室的初步数据表明，CB2激动剂在小鼠和人类乳腺癌细胞中都具有直接的抗肿瘤作用。在本提案中，我们将探讨以下假设：CB2激动剂可以采取多种有益的作用来减轻乳腺癌引起的骨痛，减少肿瘤诱导的骨骼破坏和断裂，并减少体外和体内乳腺癌细胞的生长。要测试的特定假设是：CB2受体激活将在乳腺癌诱发的骨癌疼痛的鼠模型中导致抗炎性，同时缺乏当前镇痛疗法看到的不良副作用。 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在降低了骨癌鼠模型中，慢性施用CB2激动剂在内的降低了IL-12，IL-6和TNF1，TNF1，5）是否会导致不良的副作用，而6）最重要的是，最重要的是，为乳腺癌造成的骨癌患者提供了新的和创新的治疗的新目标。迫切需要新的治疗方法，这将导致足够的疼痛缓解，而无需使当前药物的CNS副作用衰弱，并抑制骨骼降解，避免了转移引起的疼痛骨折并导致疾病的修饰。这些研究可能为制定策略的发展提供了新的机会，以治疗乳房转移到骨骼的转移以及对其他骨癌的应用。公共卫生相关性：乳腺癌是北美女性最常见的恶性肿瘤。在美国，每年有近200,000名妇女被诊断出，因此在疼痛治疗乳腺癌患者方面非常需要新的治疗干预措施。乳腺癌通常会转移到骨骼中，导致疼痛，骨骼重塑和最终骨折，导致疼痛无能为力，有限或总丧失迁移率。美国国立卫生研究院估计2006年美国癌症的总体成本为2063亿美元，直接医疗费用为782亿美元（Arrowhead Publishers，2008年）。不幸的是，当前的疗法会导致不必要的副作用，甚至促进骨骼和超敏反应的进一步恶化。该提案解决了CB2激动剂是否会减弱乳腺癌引起的骨痛，而不会导致当前镇痛治疗的不良副作用。 CB2受体在免疫细胞和调节骨骼质量但未调节中枢神经系统神经元的细胞上发现。用激动剂的CB2受体的激活抑制了几种促进疼痛的炎症因子，显着减轻了由于骨癌引起的自发疼痛，抑制骨骼的降解并减少骨骼内乳腺癌细胞的增殖。然而，CB2激动剂并未产生不必要的副作用，例如便秘，脾气暴躁，呼吸道抑郁，镇痛耐受性或奖励“成瘾”效应。