Fenretinide as an anti-angiogenic agent in neuroblastoma

Angiogenesis is a critical event in the progression of human neuroblastoma. This mini-review summarizes our literature and experimental data concerning the use of anti-angiogenic molecules, such as TNP-470 and fenretinide, in neuroblastoma treatment.     

骨肉瘤抗血管生成靶向治疗的研究进展

骨肉瘤是常见且高度恶性的原发性骨肿瘤,其治疗面临复发和转移的挑战,迫切需要探索新的骨肉瘤靶向治疗药物。该文聚焦于靶向新生血管形成的治疗策略,特别是针对血管内皮生长因子的抗血管生成治疗。综述了不同骨肉瘤抗血管生成药物在骨肉瘤治疗中的作用机制、临床效果及潜在的副作用。这些药物能有效抑制肿瘤增殖,但存在耐药性和不良反应的问题。通过对现有药物的分析和比较,为临床应用提供指导,并为骨肉瘤的治疗提供新思路。     

Thalidomide is anti-angiogenic in a xenograft model of neuroblastoma

Thalidomide has previously been shown to have anti-angiogenic properties. More recently, clinical efficacy of this agent has been demonstrated in multiple myeloma and prostate cancer. Neuroblastoma is the most frequent solid tumor of the abdomen of childhood, yet children with this disease frequently have metastases at presentation. Such patients have a very poor prognosis with current therapies. Thus, new approaches are needed. We have previously shown that VEGF antagonists can inhibit neoangiogenesis and tumor growth in experimental neuroblastoma. In this study, we investigated the anti-angiogenic and anti-tumor properties of thalidomide in a xenograft model of human neuroblastoma. Tumors were induced in athymic mice using the human neuroblastoma cell line NGP. Intraperitoneal thalidomide (100 mg/kg/dose) or vehicle was administered beginning one week after implantation, and animals euthanized at six weeks. Thalidomide treatment did not significantly alter tumor growth as compared with controls. However, thalidomide suppressed angiogenesis, as demonstrated both by fluorescein angiography and immunohistochemical staining, and induced apoptosis of endothelial cells in neuroblastoma xenografts. Quantification of microvessel density demonstrated a significant reduction of vasculature in treated tumors (p<0.004). Thalidomide induced co-option of host vasculature, an effect noted previously after VEGF blockade. This study demonstrates that thalidomide has anti-angiogenic properties in experimental neuroblastoma.     

Surrogate biomarkers for anti-angiogenic therapy for advanced colorectal cancer

Vascular endothelial growth factor (VEGF)—over-expressed in colorectal cancer—is associated with disease progression and inferior survival. Based on successful, randomized, phase III trials, anti-VEGF therapeutics have entered clinical practice. Bevacizumab, a VEGF-specific antibody, was the first anti-angiogenic agent to be approved by the Food and Drug Administration to be used in combination with standard chemotherapy in the first and second line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also normalize tumor vasculature thereby leading to greater tumor oxygenation (a known radiosensitizer) and drug penetration. A dose-escalation phase I trial has demonstrated that the combination of bevacizumab at the 5-mg/kg dose with radiochemotherapy was well tolerated by patients with rectal cancers. In addition, results from an array of correlative studies have demonstrated that bevacizumab has antivascular effects and supported the normalization hypothesis. The ongoing phase II study will further elucidate the mechanisms of action and efficacy of bevacizumab in locally advanced rectal cancer.     

Proton-beam therapy for olfactory neuroblastoma

PURPOSE: To analyze the feasibility and efficacy of proton-beam therapy (PBT) for olfactory neuroblastoma (ONB) as a definitive treatment, by reviewing our preliminary experience. Olfactory neuroblastoma is a rare disease, and a standard treatment strategy has not been established. Radiation therapy for ONB is challenging because of the proximity of ONBs to critical organs. Proton-beam therapy can provide better dose distribution compared with X-ray irradiation because of its physical characteristics, and is deemed to be a feasible treatment modality. METHODS AND MATERIALS: A retrospective review was performed on 14 patients who underwent PBT for ONB as definitive treatment at the National Cancer Center Hospital East (Kashiwa, Chiba, Japan) from November 1999 to February 2005. A total dose of PBT was 65 cobalt Gray equivalents (Gy(E)), with 2.5-Gy(E) once-daily fractionations. RESULTS: The median follow-up period for surviving patients was 40 months. One patient died from disseminated disease. There were two persistent diseases, one of which was successfully salvaged with surgery. The 5-year overall survival rate was 93%, the 5-year local progression-free survival rate was 84%, and the 5-year relapse-free survival rate was 71%. Liquorrhea was observed in one patient with Kadish's stage C disease (widely destroying the skull base). Most patients experienced Grade 1 to 2 dermatitis in the acute phase. No other adverse events of Grade 3 or greater were observed according to the RTOG/EORTC acute and late morbidity scoring system. CONCLUSIONS: Our preliminary results of PBT for ONB achieved excellent local control and survival outcomes without serious adverse effects. Proton-beam therapy is considered a safe and effective modality that warrants further study.     

Monoclonal antibody-based therapy for neuroblastoma

Dose-intensive combination chemotherapy can improve the clinical response of many pediatric solid tumors. However, cure remains elusive. Stage 4 neuroblastoma stands out as an exception. Part of this success is a result of antibody-based strategies, which include immunomagnetic purging of autologous marrow prior to autologous marrow transplantation and immunotherapy directed at minimal residual disease. It is striking that treatment with monoclonal antibodies, even when targeted at a single antigen, namely, ganglioside G_D2, can affect longterm progression-free survival among these patients. The potential role of the idiotype network in tumor control can be exploited clinically. The genetic engineering of these antibodies into novel forms holds great promise for more specific and effective targeting possibilities, including the delivery of cytokines and cells. Preclinical results are also promising. It is expected that the availability of novel antibodies directed at a broader spectrum of pediatric solid tumors will facilitate the successful application of this approach to more patients. Experience with metastatic neuroblastoma has provided proof of this principle. It is likely that other tumors will fall.     

Modes of resistance to anti-angiogenic therapy

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.     

抗肿瘤血管治疗

抗肿瘤血管治疗具有高效、抑瘤谱广、不易产生耐药和无明显毒副作用等优势。近年来抗肿瘤血管治疗的常用策略是干扰血管生成调节因子从而抑制血管生成;由于肿瘤血管内皮细胞与正常血管内皮细胞存在质的区别,具有免疫原性,抗肿瘤血管免疫治疗有望成为另一种新方法。现综述抗肿瘤血管治疗的优势、主要策略和存在的不足。     

Recent advances in anti-angiogenic therapy of cancer

Since angiogenesis is critical for tumor growth and metastasis, anti-angiogenic treatment is a highly promising therapeutic approach. Thus, for over last couple of decades, there has been a robust activity aimed towards the discovery of angiogenesis inhibitors. More than forty anti-angiogenic drugs are being tested in clinical trials all over the world. This review discusses agents that have approved by the FDA and are currently in use for treating patients either as single-agents or in combination with other chemotherapeutic agents.     

Intraoperative radiation therapy for high-risk pediatric neuroblastoma

PURPOSE: To evaluate the efficacy of intraoperative radiation therapy (IORT) in the treatment of high-risk pediatric neuroblastoma. METHODS AND MATERIALS: Between 1986 and 1998, 23 children received IORT for pediatric neuroblastoma. Electron beam energies ranged from 4 MeV to 16 MeV and median dose was 10 Gy (7-16 Gy). RESULTS: Twenty-one of 23 patients were classified as high-risk. A gross total resection (GTR) was achieved in 18 patients, of whom 6 experienced disease recurrence, 2 of which included a locoregional relapse as a component of failure. Fourteen of 18 patients receiving IORT after a GTR are disease-free survivors. A second subset of 5 patients had a subtotal resection (STR), with gross residual disease remaining after surgery. All 5 patients recurred locally, and all died of their disease. IORT was extremely well-tolerated in our cohort. Surgical resection and IORT resulted in the narrowing of the abdominal aorta and an atrophic kidney in 1 patient. CONCLUSIONS: For high-risk neuroblastoma patients, IORT as the only radiotherapy to the primary, produced excellent local control after a GTR. However, IORT as the sole radiotherapy to the primary was inadequate for patients with extensive adenopathy or an STR. In this setting, we are exploring the use of IORT as a boost in conjunction with external beam radiation therapy.     

An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma

Recent clinical trial results suggest that anti-angiogenic therapy may be effective against recurrent malignant glioma. Though these treatments prolong progression-free survival, the extent to which they prolong overall survival is unknown. We pooled data from 34 patients treated at a single institution on phase II clinical trials of bevacizumab and cediranib, and we compared these data to 18 patients treated on clinical trials of cytotoxic chemotherapies. In univariate and multivariate analyses, treatment group was a significant predictor of progression-free but not overall survival. Median progression-free survival was 8 vs. 22 weeks in patients treated with cytotoxic as compared to anti-angiogenic therapy (P = 0.01). Median overall survival was nearly identical in the two groups (39 vs. 37 weeks). The results of this exploratory analysis suggest that anti-angiogenic therapy may fail to prolong overall survival in patients with recurrent malignant glioma. If this conclusion proves correct, progression-free survival may be an inappropriate endpoint for phase II trials of anti-angiogenic therapies.     

NSAIDs in neuroblastoma therapy

Cyclooxygenases (COX) catalyse the conversion of arachidonic acid to prostaglandins. COX-2 is upregulated in several adult epithelial cancers. In neuroblastoma it has been shown that the majority of primary tumours and cell lines express high levels of COX-2, whereas normal adrenal medullas from children do not express COX-2. Treatment of neuroblastoma cells with nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of COX, induces caspase-dependent apoptosis via the intrinsic mitochondrial pathway. Established neuroblastoma xenografts in nude rats treated with the dual COX-1/COX-2 inhibitor, diclofenac, or the COX-2 specific inhibitor, celecoxib significantly inhibits neuroblastoma growth in vivo. In vitro, arachidonic acid and diclofenac synergistically induces neuroblastoma cell death. This effect is further pronounced when lipoxygenases is inhibited simultaneously. Proton MR-spectroscopy (1H MRS) of neuroblastoma cells treated with COX-inhibitors demonstrates accumulation of polyunsaturated fatty acids and depletion of choline compounds. Thus, 1H MRS, which can be performed with clinical MR-scanners, is likely to provide pharmacodynamic markers of neuroblastoma response to COX-inhibition. Taken together, these data suggest the use of NSAIDs as a novel adjuvant therapy for children with neuroblastoma.     

非小细胞肺癌抗血管生成治疗的预测及预后指标

目前,非小细胞肺癌（non-small-cell lung cancer,NSCLC）已成为癌症相关死亡的首要原因。血管生成（angiogenesis）,即新生血管形成,是一个严格而复杂的调控过程,可促进肺癌及其它恶性肿瘤疾病进展和远处转移。抗血管生成治疗（anti-an? giogenic therapy）是以新生血管为靶点的抗肿瘤方法。目前临床上常用的细胞毒药物作用于所有快速分裂的细胞,可导致严重治疗副作用如免疫抑制、胃肠道反应和脱发等。而除子宫内膜外新生血管形成很少发生于健康成年人,因此相对而言,抗血管生成治疗理论上副作用较少,在临床上应用具有良好的前景。由于不同个体发生的肿瘤其血管生成可能是由不同的血管生成因子调控,因此,在抗血管生成药物越来越多的今天,正确地选择患者个体,选择有针对性的治疗非常重要。本文回顾了非小细胞肺癌抗血管生成药物的预测及预后指标的临床研究及相关指标基本原理的临床前研究。      

Molecular diagnosis of tumor angiogenesis and anti-angiogenic cancer therapy

Angiogenesis is regulated by the balance of pro-angiogenic factors and angiogenesis inhibitors, and the imbalance of these regulators is the cause of pathological angiogenesis, including tumor angiogenesis. Angiogenesis is required for tumor growth and metastasis, and thus constitutes an important target for the control of tumor progression. While the benefit of anti-angiogenic therapy is potentially profound, limitations have also been recognized by the results obtained thus far by clinical trials. Precise understanding of the process of angiogenesis should lead us to new regimens for more efficient anti-angiogenic therapy. This review focuses on our current understanding of the molecular mechanism of tumor angiogenic and the status of the anti-angiogenesis approach for cancer treatment.     

Angiogenesis and anti-angiogenic therapy in myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem cell disorder that is characterized by florid bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis. Almost all patients with MMM display increased bone marrow microvessel density (MVD) and the extent is among the highest in hematological malignancies. This particular information has encouraged the therapeutic use of anti-angiogenic drugs in MMM. In the current review, we summarize the general concepts regarding angiogenesis, assessment of angiogenesis in hematological malignancies and then the current literature on angiogenesis and anti-angiogenic therapy in MMM.     

Retinoid therapy of high-risk neuroblastoma

Retinoids are derivatives of vitamin A that include all trans-retinoic acid (ATRA), 13-cis-retinoic acid, (13-cis-RA), and fenretinide (4-HPR). High levels of either ATRA or 13-cis-RA can cause arrest of cell growth and morphological differentiation of human neuroblastoma cell lines, and phase I trials showed that higher and more sustained drug levels were obtained with 13-cis-RA relative to ATRA. A phase III randomized trial showed that high-dose, pulse therapy with 13-cis-RA given after completion of intensive chemoradiotherapy (with or without autologous bone marrow transplantation) significantly improved event-free survival in high-risk neuroblastoma. The cytotoxic retinoid 4-HPR achieved multi-log cell kills in neuroblastoma cell lines resistant to ATRA and 13-cis-RA, and a pediatric phase I trial has shown it to be well tolerated. Cytotoxicity of 4-HPR is mediated at least in part by increasing tumor cell ceramide levels and combining 4-HPR with ceramide modulators increased anti-tumor activity in pre-clinical models. Thus, further clinical trials of 4-HPR in neuroblastoma, and of 4-HPR in combination with ceramide modulators, are warranted.