前列腺癌骨转移机制和骨靶向药物研究进展

骨是前列腺癌最常见的晚期转移部位，骨微环境和前列腺癌中多种细胞因子如核因子-κB受体活化因子配体(Receptor activator of NF-κB ligand, RANKL)、趋化因子家族、整合素等通过复杂的相互作用机制参与了前列腺癌骨转移。多种骨靶向药物如二磷酸盐、地诺单抗和放疗药物如镭-223被批准用于预防和治疗因前列腺癌骨转移引起的骨骼相关事件(Skeletal-related events, SREs)。本文对前列腺癌骨转移的生物学机制和骨靶向药物研究进展进行综述。     

前列腺癌骨转移机制及新型靶向治疗的最新研究进展

前列腺癌是唯一最先发生骨转移而非内脏转移的实体肿瘤,骨转移在临床上十分常见,不仅降低了患者总生存期和生活质量还增加了治疗负担。目前二磷酸盐和地诺单抗是骨转移的标准治疗药物,但总体治疗效果有限。近年来随着对骨转移分子机制的进一步研究,出现了许多骨靶向治疗的新药。本文就其骨转移的“恶性循环”机制及针对骨转移潜在作用靶点开展临床研究和试验的骨靶向药物进展作一综述。     

骨转移癌分子靶向治疗进展

常见恶性肿瘤患者不但骨转移的发生率较高,而且骨相关事件（skeletal related events,SRE）也频繁出现,严重影响着患者的生活质量。双膦酸盐是肺癌骨转移全身治疗的基础用药,能将首次发生骨相关事件的中位时间平均延迟2～3个月,但患者的肾功能状况及不良反应限制了其在临床中的应用。随着骨转移癌机制研究的深入,越来越多的临床前或临床研究验证了靶向药物如地诺单抗等在延迟乳腺癌、前列腺癌、多发性骨髓瘤和其他实体肿瘤骨转移癌所致骨相关事件的发生方面优效于双膦酸盐。     

《中国肿瘤临床》文章推荐:恶性肿瘤骨转移靶向治疗及免疫治疗进展

恶性肿瘤的骨转移严重威胁癌症患者的生活质量与生存获益,而放疗等传统抗肿瘤治疗手段对于骨转移灶的疗效不够理想,仅能起到对于局部病灶的控制作用。近年来,双膦酸盐类药物及地诺单抗等靶向药物有效降低了骨相关不良事件的发生率,并且对于部分癌种提高了骨转移患者的生存获益。随着肿瘤免疫疗法的突破,探索免疫检查点阻断和其他潜在骨转移灶免疫治疗靶点的应用价值给骨转移患者的治疗带来新的希望。     

恶性肿瘤骨转移靶向治疗及免疫治疗进展

恶性肿瘤的骨转移严重威胁癌症患者的生活质量与生存获益,而放疗等传统抗肿瘤治疗手段对于骨转移灶的疗效不够理想,仅能起到对于局部病灶的控制作用。近年来,双膦酸盐类药物及地诺单抗等靶向药物有效降低了骨相关不良事件的发生率,并且对于部分癌种提高了骨转移患者的生存获益。随着肿瘤免疫疗法的突破,探索免疫检查点阻断和其他潜在骨转移灶免疫治疗靶点的应用价值给骨转移患者的治疗带来新的希望。本文重点针对恶性肿瘤骨转移的靶向治疗及免疫治疗进展进行综述。      

地诺单抗治疗骨巨细胞瘤的研究进展

骨巨细胞瘤是一种以溶骨性破坏为特征的侵袭性肿瘤,手术治疗后复发率高,少数会出现肉瘤样恶变及转移。近年来,针对特异性靶向核因子κB受体活化因子配体(receptor activator of nuclear factor kappa B ligand,RANKL)的地诺单抗治疗高级别、不可切除和转移性骨巨细胞瘤疗效显著,能够降低外科分期,增加手术切除几率,减少术后功能丧失,控制肿瘤进展;同时,用药后影像及病理学出现特征性改变,对临床诊断及手术治疗提出新的问题。最后,地诺单抗在用药时间、安全性方面尚有部分争议,有待进一步临床试验证实。      

骨改良药物在乳腺癌骨转移治疗中的应用进展

骨改良药物包括在临床上应用的双膦酸盐及2010年FDA批准上市的新药地诺单抗,是目前治疗恶性肿瘤骨转移、高钙血症及骨质疏松症的主要药物。该类药物在临床上应用广泛,种类较多,近年来在药物的应用时机、用法及毒副反应方面有一定进展和争议。本文就骨改良药物在乳腺癌骨转移治疗中的临床应用进行探讨。     

地舒单抗在骨肿瘤/骨病的非适应证用药现状

地舒单抗是一种针对核因子κb配体（RANKL）的单克隆抗体，可显著抑制破骨细胞活性，已被批准用于治疗骨质疏松症、骨巨细胞瘤以及预防和治疗实体瘤骨转移。RANKL/RANK/OPG的失衡也与其他几种罕见的骨病和类肿瘤疾病的发病机制有关，包括动脉瘤样骨囊肿、骨纤维异样增殖症、朗格汉斯细胞组织细胞增多症等。虽在这些疾病中，并没有获得适应证批准，但在临床上已有很多相关报道。本综述总结现有的地舒单抗在代谢性骨病和类肿瘤疾病中的适应证以外使用的证据，为临床诊治提供参考。     

实体瘤骨转移靶向治疗进展

多种实体瘤如乳腺癌、前列腺癌等在远处转移时具有明显的趋骨性.骨转移可严重影响患者的生活质量,并间接影响患者的生存.目前二磷酸盐和地诺单抗是骨转移的标准治疗药物,但总体治疗效果有限.随着骨转移分子机制研究的进展,近年出现了多种新兴靶向治疗药物.本文旨在根据靶向目标及机制的不同,对已在实体瘤骨转移中开展临床研究和试验的靶向治疗进展作一概述.     

地诺单抗在骨巨细胞瘤治疗中的应用研究进展

正2013年,美国食品药品监督局(FDA)正式批准denosumab(地诺单抗,商品名叫Xgeva或Prolia)用于复发、手术不可完全切除及发生转移的骨巨细胞瘤(giant cell tumor,GCT)患者的临床治疗[1]。denosumab作为全人源性单克隆抗体,对外科手术无法干预的GCT患者有着很好的疗效及生物安全性。笔者通过将"denosumab"、"RANKL"、"骨巨细胞瘤"、"骨相关事件"等作为关键词,计算机检索数据库Pubmed、EMBASE、中国知网、维普中文科技期刊数据库,重点回顾近5年来关于denosumab的作用机制及在治疗GCT的临床应用和最新研究进展。一、GCT1.流行病学概况:目前认为GCT多数具有局部侵袭     

RANKL inhibition: a promising novel strategy for breast cancer treatment

The cytokine RANKL and its receptor RANK, key proteins in bone remodelling and bone metastasis, are essential for mammary gland development in mice. RANK absence or overexpression results in a lactation defect and a non-functional mammary gland. RANKL signalling mediates progesterone-induced proliferation and expansion of the stem cell compartment in the mouse mammary gland. RANK overexpressing mammary epithelial acini show hallmarks of transformation in a RANKL-dependent manner. Complementary gain- and loss-of-function approaches (RANK transgenic and knock-out mouse models and pharmacological RANKL inhibition) define a direct contribution of this pathway to progestin-driven mammary cancer. Moreover, decreased RANKL signalling attenuates preneoplasic lesions and lung metastasis in the spontaneous model of mammary tumorigenesis MMTV-neu, suggesting that RANK pathway promotes mammary tumorigenesis and metastasis in a wider tumour spectrum and beyond its established role in bone metastasis. In this review, we summarise the role of the RANKL pathway in mammary gland development, breast cancer and metastasis, and discuss the potential application of RANKL inhibition for breast cancer treatment.     

Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma.

During normal bone remodeling, the receptor activator of nuclear factor-kappaB (RANK) interacts with its ligand RANKL, which is present on pre-osteoclasts, resulting in bone resorption and initiation of new bone formation. When breast cancer metastasizes to bone, normal bone remodeling is disturbed by invasion of tumor cells, resulting in osteolytic lesions. We have studied the expression of both RANK and RANKL in 10 nonneoplastic breast samples, 58 infiltrating ductal carcinoma (IDC), and 43 breast cancer bony metastases (BTM). RANK seemed to be present in all samples tested. However, whereas RANKL expression was observed in 90% of nonneoplastic breast, RANKL expression was only observed in 62% of nonmetastatic IDC, 31% of metastatic IDC, and 2% of osteolytic BTM lesions. This decreased or absent expression of RANKL in the tumor cells may allow RANK, which is normally expressed as a receptor on the cell surface, to target RANKL present on the cell surface of normal osteoblasts and stromal cells of the bone. Stimulation of the normal osteoblasts and stromal cells by the tumor cells may then lead to secondary osteoclastogenesis, resulting in the osteolytic phenotype common to breast metastases.     

The role of RANK/RANKL/osteoprotegerin (OPG) triad in cancer-induced bone diseases: physiopathology and clinical implications

Bone homeostasis is maintained by the remodelling of bone which depends on a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Malignant bone lesions are very common in patients with cancer; whether they result from a tumor in bone (giant cell tumour of bone, osteosarcoma, multiple myeloma...) or they are bony metastases from advanced cancers of which the most osteotropic are breast and prostate cancer. Malignant cells within the bone disrupt the normal bone remodelling process, leading to increased bone destruction and occurence of pathological fractures. Receptor activator of NF-kB (RANK) and its ligand (RANKL) play a pivotal role in the regulation of bone remodelling; by binding to RANK, RANKL stimulates osteoclastogenesis and bone resorption, whereas its cognate decoy receptor osteoprotegerin (OPG) blocks this process by interacting with RANKL. Tumour cells produce different factors that manipulate the RANK/RANKL/OPG pathway in order to stimulate bone destruction. Furthermore, pending on the tumour type, RANKL plays a role in the migration, invasion and proliferation of malignant cells within the bone, while OPG increases survival of tumour cells. Inhibition of RANK/RANKL system may therefore offer new therapeutic perspectives for the treatment of primitive and secondary bone cancers.     

Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis

Receptor activator of nuclear factor-kappa B ligand (RANKL) is a TNF ligand superfamily member that is essential for the formation, activation, and function of osteoclasts. RANKL functions via its cognate receptor RANK, and it is inhibited by the soluble decoy receptor osteoprotegerin (OPG). In skeletal metastases, the ratio of RANKL to OPG is upregulated, which leads to increased osteoclast-mediated bone destruction. These changes in the bone microenvironment not only compromise the structural integrity of bone, leading to severe clinical morbidities, but have also been implicated in establishment of de novo bone metastasis and the progression of existing skeletal tumors. Evaluation of RANKL inhibitors, including the fully human anti-RANKL antibody denosumab, in patients with cancer has shown reductions in tumor-induced bone resorption activity and successful management of skeletal complications of bone metastases. RANKL also functions as a major paracrine effector of the mitogenic action of progesterone in mouse mammary epithelium, and it has a role in ovarian hormone-dependent expansion and regenerative potential of mammary stem cells. RANKL inhibition attenuates mammary tumorigenesis and pulmonary metastases in mouse models. These data suggest that the contribution of progesterone to increased mammary cancer incidence is mediated, at least in part, by RANKL-dependent changes in the mammary epithelium; RANKL also directly promotes distant metastases. In summary, the antitumor and antimetastatic effects of RANKL inhibition can occur by at least 2 distinct mechanisms, one in the bone via osteoclast-dependent effects, and the second via direct effects on the tumor cells of various origins and/or mammary epithelium.     

RANKLed by the Complexity of Signaling in Breast Cancer Metastasis to the Brain

BackgroundReceptor activator of nuclear factor κB (RANK) and its ligand, RANKL, are essential for mammary gland development and play a vital role in breast carcinogenesis. RANKL-RANK signaling also drives thermoregulation and modulates inflammatory activation in the brain. The expression of RANKL in primary breast cancer (BC) has been negatively associated with brain metastases, while significantly higher levels of RANK are seen in BC with brain metastases. We examined the expression of RANK and RANKL in BC metastasis to the brain.Patients and MethodsWe examined the expression of RANK and RANKL in 40 cases of BC metastasis to the brain.ResultsRANK was variably expressed in BC cells but minimally expressed in the adjacent brain parenchyma. In contrast, the expression of RANKL was minimal in metastatic BC but highly variable in tumoral stroma. RANKL expression in normal brain stroma obtained during autopsy was negligible. Histologic grade and BC subtypes were not significantly associated with RANK expression in metastatic BC. A significant negative correlation between RANK in metastatic BC and RANKL in tumoral stroma was identified (P < .001).ConclusionRANK expressed by primary BC and RANKL detected in the tumor microenvironment together participate in cancer development, while the same principle may operate at distant sites. Further investigation is necessary to provide additional insight into the role of the RANKL-RANK pathway in BC progression and to investigate the potential efficacy of therapeutic strategies targeting these molecules in BC metastasis to the brain.     

Anti-RANKL antibody for treatment of patients with bone metastasis from breast cancer

Breast cancer is known to be associated with a high incidence of bone metastases. Recent advances in treatment for breast cancer have improved patient prognosis, including those with bone metastasis, highlighting the importance of treating bone metastasis to reduce incidence of skeletal complications and to improve patients' QOL. Currently, bisphosphonates(BP), which are recommended by domestic and international clinical practice guidelines, are commonly used for the treatment of bone metastasis. However, the outcomes of BP therapy leave room for improvement in regard to their efficacy, safety, and convenience. Prior studies have indicated that RANK ligand(RANKL), a cytokine mainly expressed in osteoblasts and bone marrow stromal cells, plays an important role in bone resorption by osteoclasts, which are key mediators in the formation and progression of bone metastasis. Denosumab is a fully human monoclonal anti-RANKL antibody which suppresses differentiation, activation, and survival of osteoclasts by inhibiting the binding of RANKL to its receptor, RANK. In a phase III clinical trial, denosumab significantly decreased the time-to-first and time-to-first-and-subsequent skeletal related events(SRE), compared with zoledronic acid in advanced breast cancer patients with bone metastases. Further more, denosumab was more effective than zoledronic acid in preventing the progression of bone pain and maintaining patients QOL. In the future, treatment of bone metastases for breast cancer patients is expected to evolve further with the introduction of denosumab, which is conveniently administered by subcutaneous injection.     

c-Src参与RANKL诱导的乳腺癌BT-474细胞迁移的机制研究

目的：核因子-κB受体活化因子配体（RANKL）/核因子κB受体活化因子（RANK）通路在肿瘤骨定向性迁移中发挥重要的作用,但具体信号传导机制尚不清楚。本文探讨非受体酪氨酸激酶c-Src在RANKL诱导的乳腺癌BT474细胞迁移中的作用。方法：Western blot检测BT-474细胞表面受体RANK蛋白的表达及RANKL刺激后细胞p-Src及c-Src的表达;Transwell法测定细胞迁移能力。采用SPSS 16.0统计学软件分析实验数据。结果：BT-474细胞表达RANK蛋白,RANKL诱导BT-474细胞迁移能力增强。应用RANKL的圈套受体OPG可阻断RANKL诱导的细胞迁移。RANKL刺激后BT-474细胞p-Src表达升高,应用c-Src激酶抑制剂PP2可显著抑制RANKL诱导的细胞迁移。结论：c-Src信号通路参与RANKL诱导的乳腺癌BT-474细胞迁移。     

RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation

Accumulating studies have shown that the receptor activator of nuclear factor-κB ligand (RANKL)/RANK pathway plays an important role in tumor metastasis. However, the involvement of the RANKL/RANK signal transduction pathway in breast cancer metastasis remains unclear. The present study, therefore, investigated the role of downstream molecules of RANKL/RANK signaling in breast cancer cells using Transwell chemotaxis assays. RANKL was shown to direct the migration of MDA-MB-231 breast cancer cells. Osteoprotegerin (OPG; soluble decoy receptor of RANKL) inhibited RANKL-induced migration. RANKL activated Src kinase in MDA-MB-231 cells, as shown by Western blotting, and pretreatment with a Src inhibitor abrogated RANKL-induced cell migration, in a similar manner to OPG. Short-hairpin RNA against RANK, delivered via a lentiviral vector, significantly abolished the expression of phosphorylated Src. Stimulation by RANKL induced the phosphorylation of mitogen-activated protein kinases (MAPKs) (ERK, p38, JNK), and specific inhibitors of MAPKs blocked RANKL-induced cell migration. Furthermore, the expression of phosphorylated MAPKs could be blocked by a Src inhibitor and by small interfering RNA against Src. These findings suggest that Src and MAPK pathways may be involved in RANKL-induced MDA-MB-231 breast cancer cell migration.     

RANK/RANKL/OPG信号通路介导神经母细胞瘤骨侵袭/转移机制的研究进展

神经母细胞瘤是第二常见的儿童颅外实体肿瘤,一般发现时70％已出现侵袭/转移,而骨侵袭/转移是其致残致死的关键原因.在这一过程中神经母细胞瘤细胞、成骨细胞及其前体细胞、破骨细胞及其前体细胞和骨髓基质细胞通过一系列相关因子促进骨侵袭/转移发生,其中RANK/RANKL/OPG通路在骨侵袭/转移过程中的作用至关重要.本文通过RANK/RANKL/OPG信号转导通路对神经母细胞瘤骨侵袭/转移机制的研究进展做一综述.