Bevacizumab--current status and future directions.

Angiogenesis is crucial to tumour initiation, survival and metastasis. Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors in cancer development. Bevacizumab (a humanised monoclonal antibody against VEGF) has a reasonable safety profile and proven efficacy in a phase III trial in advanced colorectal cancer. Efficacy of Bevacizumab also looks promising in non small cell lung cancer, renal cancer and a variety of other solid tumours. Questions still surround optimal dosing and the appropriate selection of patients who are most likely to benefit. Future trials will address these questions and provide further translational insights.     

Antiangiogenesis agents in the treatment of soft tissue sarcomas

Soft tissue sarcomas (STSs) are a heterogeneous group of malignancies that includes >50 different subtypes, each with unique clinical and pathologic qualities. In general, there is a 50% cure rate, and most cures are achieved with complete surgical resection with or without radiation therapy. The results from chemotherapeutic agents for unresectable or metastatic disease have been disappointing with minimal long‐term benefit. New targeted and novel agents are needed to improve response and survival. Tumor angiogenesis has been an intense focus in cancer therapy over the past decade. Several of numerous antiangiogenesis agents have been developed, and many already have been approved for the treatment of both solid and liquid tumors. Certain STSs are highly vascular tumors that often demonstrate angiogenesis markers. The objective of this review was to evaluate these angiogenesis markers in defining the role of angiogenesis in the treatment of patients with STS. In addition, the authors conducted an in‐depth review of the results from using key antiangiogenesis agents in the treatment of STS. Cancer 2010. © 2010 American Cancer Society.     

Ewing sarcoma: prognostic criteria,outcomes and future treatment

Ewing sarcoma (EWS) is a bone tumor occurring primarily in adolescence and young adulthood. Multi-institutional clinical trials have improved the outcome for patients with nonmetastatic EWS, but not with metastatic EWS. Furthermore, although 30% of EWS recur, multi-institutional studies have not been completed for this high-risk group. Planning such studies has been hampered by both the lack of novel therapies and the inability to incorporate the biology of EWS. While the importance and detail of the EWS-FLI-1 translocation between chromosomes 11 and 22 are described, these have not yet led to new drug development for this orphan tumor. However, recent evidence supporting novel cytotoxic therapy, antiangiogenic therapy, and receptor-targeted therapy provides reason for optimism for patients with high-risk disease.     

Hypoxia shifts activity of neuropeptide Y in Ewing sarcoma from growth-inhibitory to growth-promoting effects

Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES.     

Angiogenesis Inhibitors as Anti-Cancer Therapy Following Renal Transplantation: A Case Report and Review of the Literature

Solid organ transplant recipients on long-term immunosuppressive medication are at increased risk of developing malignancy, and treatment of advanced cancers with angiogenesis inhibitors in this context has not been widely studied. We present a case of recurrent high-grade serous ovarian carcinoma treated with paclitaxel and bevacizumab in the context of prior renal transplantation where the patient responded well to treatment with controlled toxicities, discussing the potential for increased rates of adverse events and drug interactions in this select population.     

Inhibition of renal cell carcinoma angiogenesis and growth by antisense oligonucleotides targeting vascular endothelial growth factor

Angiogenesis is critical for growth and metastatic spread of solid tumours. It is tightly controlled by specific regulatory factors. Vascular endothelial growth factor has been implicated as the key factor in tumour angiogenesis. In the present studies we evaluated the effects of blocking vascular endothelial growth factor production by antisense phosphorothioate oligodeoxynucleotides on the growth and angiogenic activity of a pre-clinical model of renal cell carcinoma (Caki-1). In vitro studies showed that treating Caki-1 cells with antisense phosphorothioate oligodeoxynucleotides directed against vascular endothelial growth factor mRNA led to a reduction in expressed vascular endothelial growth factor levels sufficient to impair the proliferation and migration of co-cultured endothelial cells. The observed effects were antisense sequence specific, dose dependent, and could be achieved at a low, non-toxic concentration of phosphorothioate oligodeoxynucleotides. When vascular endothelial growth factor antisense treated Caki-1 cells were injected into nude mice and evaluated for their angiogenic potential, the number of vessels initiated were approximately half that induced by untreated Caki-1 cells. To test the anti-tumour efficacy of vascular endothelial growth factor antisense, phosphorothioate oligodeoxynucleotides were administrated to nude mice bearing macroscopic Caki-1 xenografts. The results showed that the systemic administration of two doses of vascular endothelial growth factor antisense phosphorothioate oligodeoxynucleotides given 1 and 4 days after the tumours reached a size of approximately 200 mm(3) significantly increased the time for tumours to grow to 1000 mm(3).     

Nitric Oxide and Angiogenesis

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell–cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.     

Clinical features and outcomes in patients with extraskeletal Ewing sarcoma

BACKGROUND:

Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES).

METHODS:

Patients <40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor reported to the United States Surveillance, Epidemiology, and End Results Program database from 1973 to 2007 were evaluated based on skeletal (n = 1519) versus extraskeletal (n = 683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated via the Kaplan‐Meier method and compared using log‐rank tests and Cox proportional hazard models.

RESULTS:

Patients with EES had a higher mean age (19.5 vs 16.3 years; P < .001) and were less likely to be male (53.4% vs 63.3%; P < .001) or white (84.8% vs 92.5%; P < .001) compared with patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs 54.2%; P = .001) but were less likely to arise specifically in the pelvis (19.8% vs 26.6%; P < .001). Metastatic status or tumor size did not differ by group. Five‐year overall survival was superior for localized EES compared with localized skeletal tumors (69.7% vs 62.6%; P = .02). The hazard ratio for death in patients with localized skeletal tumors compared with localized EES was 2.36 (95% confidence interval, 1.61‐3.44) beyond 24 months from initial diagnosis.

CONCLUSIONS:

Patient characteristics and outcomes differ among patients with EES compared with patients with skeletal Ewing sarcoma. These findings may have important implications for patient care. Cancer 2011. © 2011 American Cancer Society.     

Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma

BACKGROUND: Local recurrence in Ewing sarcoma is associated with a poor prognosis. The purpose of the study was to determine the factors that predict local recurrence after surgical treatment of the primary tumor. METHODS: Between 1990 and 2001, 64 patients underwent surgical resection of Ewing sarcoma. Surgical margins were assessed histologically and radiologically. Response to preoperative chemotherapy was determined by detailed specimen mapping. Local recurrence-free survival (LRFS) was calculated by Kaplan-Meier analysis. Multivariate analysis was performed with the Cox proportional hazards model. RESULTS: A number of factors were found to be associated with local recurrence on univariate analysis. Patients with a good response to chemotherapy (> or = 90% tumor necrosis), had superior LRFS at 5 years (86% vs 51%, P = .015). Central site of disease was associated with an increased rate of recurrence. The LRFS at 5 years was 50% for the chest wall, 74% for pelvic/scapular, and 86% for extremity tumors (P = .083). Positive surgical margin was not a strong predictor of recurrence (P = .72). A critical analysis of minimal surgical margin based on preoperative magnetic resonance imaging (MRI) and computed tomography (CT) scans also failed to reveal an association between margin and local recurrence. In multivariate analysis, the 2 independent predictors of local recurrence were histological response to chemotherapy and central site of disease. CONCLUSION: Local recurrence after surgical resection is a complex phenomenon. An important predictive factor is the response to chemotherapy. In the current study, this seems to have the largest impact. Central site of disease may be a second independent predictive factor.     

Ewing sarcoma in adults treated with modern radiotherapy techniques

Background and purposeTo evaluate local control and survival outcomes in adults with Ewing sarcoma (ES) treated with radiotherapy (RT).Material and methodsRetrospective review of all 109 patients age ⩾18 treated for ES with RT to the primary site at Memorial Sloan Kettering Cancer Center between 1990 and 2011. RT was used as the definitive local control modality in 44% of patients, preoperatively for 6%, and postoperatively for 50%.ResultsMedian age at diagnosis was 27 years (range, 18–67). The 5-year local failure (LF) was 18%. Differences in LF were not identified when evaluated by modality of local control (RT versus combined surgery and RT), RT dose, fractionation, and RT technique. However, margin status at time of resection significantly predicted LF. The 5-year event-free survival and overall survival rates were 44% and 66% for patients with localized disease, compared with 16% and 26% for metastatic disease (p = 0.0005 and 0.0002). Tumor size, histopathologic response to chemotherapy, and treatment on or according to a protocol were also significantly associated with survival.ConclusionsThis series of adults treated with modern chemotherapy and RT had prognostic factors and outcomes similar to adolescents with ES. All adults with ES should be treated with an aggressive, multidisciplinary approach.     

Risk stratification and pattern of cardiotoxicity in pediatric Ewing sarcoma

Introduction

Anthracycline chemotherapy contributes to improved outcomes in Ewing sarcoma; however, the most feared complication is cardiotoxicity. Echocardiograms were routinely used to monitor cardiac function after anthracycline treatment. Nevertheless, indices chosen to assess cardiac toxicity vary significantly among different centers, and no uniform protocol has been accepted as ideal.

Bevacizumab and glioblastoma: Scientific review,newly reported updates,and ongoing controversies

Anti‐angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti‐glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma. Cancer 2015;121:997–1007. © 2014 American Cancer Society.     

Clinical outcome of children and adults with localized Ewing sarcoma

BACKGROUND:

As Ewing sarcoma (EWS) can affect children and adults, these patients can be treated at either a pediatric or an adult institution. This study investigated whether differences in therapeutic strategy undertaken in pediatric and adult specialty sarcoma centers correlated with clinical outcome.

METHODS:

Data from patients with localized EWS treated between 1990 and 2005 at tertiary care pediatric and adult institutions were reviewed.

RESULTS:

Fifty‐three patients (24 adult and 29 pediatric) were treated. Pediatric patients received a median of 16 cycles of chemotherapy comprised of doxorubicin, vincristine, cyclophosphamide, ifosfamide, and etoposide. Adult patients received a median of 10 cycles of treatment, and a significantly lower total cumulative dose of ifosfamide and cyclophosphamide (P < .0001). There was no difference noted with regard to the total dose of doxorubicin, or in the type of local therapy offered (surgery or radiotherapy, vs both). However, local therapy occurred earlier in pediatric patients compared with adults (3.7 months vs 7.4 months; P = .0003). The 3‐year event‐free survival (EFS) rate in pediatric and adult patients was 70% ± 9% and 43% ± 13% (P = 0.1), respectively. The 3‐year overall survival rate was 81% ± 7.7% and 59% ± 12% (P = .02) for pediatric and adult patients, respectively. Factors found to be significantly associated with EFS on univariate analysis included pelvic site, cyclophosphamide dose, and time to local therapy. On multivariate analysis, only pelvic disease (hazard ratio [HR] 4.26; P = .018) and time to local therapy (HR, 1.19; P = .002) were found to be significant.

CONCLUSIONS:

Adults with localized EWS have an inferior outcome compared with pediatric patients. This difference may be related to lower doses of alkylating agents and the timing of local therapy. Cancer 2010. © 2010 American Cancer Society.     

The Contributions of Cyclooxygenase-2 to Tumor Angiogenesis

Cyclooxygenase-2 (COX-2) is an immediate early response gene that can be induced by a variety of tumor promoters, cytokines, growth factors and hypoxia. COX-2 overexpression is linked to all stages of carcinogenesis with the enzyme localized to the neoplastic cells, microvascular endothelial cells, and stromal fibroblasts. The contributions of COX-2 in tumor angiogenesis include: (a) the increased expression of the proangiogenic growth factor VEGF; (b) the production of the eicosanoid products thromboxane A₂, PGE₂ and PGI₂ that can directly stimulate endothelial cell migration and growth factor-induced angiogenesis; and potentially, (c) the inhibition of endothelial cell apoptosis by stimulation of Bcl-2 or Akt activation. Selective pharmacological inhibitors of COX-2 as angiosuppressive agents could have therapeutic benefit in the treatment of neoplastic disease from prevention through treatment of advanced metastatic disease. These agents are safe and well tolerated and can be added to chemotherapy and radiation therapy where angiogenesis inhibitors appear to provide at least additive therapeutic benefit.     

Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells

In various cell types, the neuro- and endocrine peptide somatostatin induces inhibitory and anti-secretory effects. Since somatostatin receptors, especially of the subtype sst2A, are constantly over-expressed in gliomas, we investigated the influence of somatostatin and the receptor subtype-selective peptide/non-peptide agonists octreotide and L-054,522 on the secretion of the most important angiogenesis factor produced by gliomas, vascular endothelial growth factor (VEGF). Cultivated cells from solid human gliomas of different stages and glioma cell lines secreted variable amounts of VEGF, which could be lowered to 25% to 80% by co-incubation with somatostatin or sst2-selective agonists (octreotide and L-054,522). These effects were dose-dependent at nanomolar concentrations. Stimulation with different growth factors (EGF, bFGF) or hypoxia considerably increased VEGF production over basal levels. Growth factor-induced VEGF synthesis could be suppressed to <50% by co-incubation with somatostatin or an sst2-selective agonist; this was less pronounced in hypoxia-induced VEGF synthesis. The effects were detected at the protein and mRNA levels. These experiments indicate a potent anti-secretory action of somatostatin or sst2 agonists on human glioma cells that may be useful for inhibiting angiogenesis in these tumors.     

Modulating sphingosine-1-phosphate receptors to improve chemotherapy efficacy against Ewing sarcoma

Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here, we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In our study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved antitumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.     

紫杉醇对尤文肉瘤细胞系诱导凋亡及生长抑制的研究

目的 研究抗微管药紫杉醇在体外实验条件下对尤氏肉瘤细胞系RD—ES的诱导凋亡及生长抑制作用。方法 不同浓度的紫杉醇作用于体外培养的RD—ES细胞，通过形态学观察，台盼兰染色，Giemsa染色，流式细胞仪分析技术，原位末端标记分析凋亡细胞DNA降解产物等方法，观察紫杉醇诱导RD—ES凋亡的作用。结果 通过与其他化疗药物比较，及随时间剂量改变的情况，可见紫杉醇对RD—ES细胞的诱导凋亡作用呈时间，剂量依赖关系，细胞分裂受阻，凋亡峰明显，多核瘤细胞增多，胞浆中空泡明显。原位末端标记可见DNA降解后的阳性反应。结论 体外诱导实验证实紫杉醇对RD—Es细胞系的有丝分裂有明显的抑制作用及诱导凋亡作用且随时间，剂量增加而增大。     

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy

BACKGROUND:

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.

METHODS:

Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m² for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m² for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).

RESULTS:

All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.

CONCLUSIONS:

Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.