Use Of Antiangiogenic Agents Research Articles

Safety of endoscopy in cancer patients on antiangiogenic agents: A retrospective multicenter outcomes study.

Background/AimsThe use of antiangiogenic agents (AAs) in cancer treatment has increased because they offer survival benefit in combination with cytotoxic chemotherapy. Given their potential to cause gastrointestinal (GI) perforation and bleeding, it is currently recommended that AAs be held for 28 days before and after surgery. However, there are no specific guidelines which address their use around endoscopic procedures because data regarding the safety of endoscopy in cancer patients while on AAs is scarce despite the fact that these patients often require endoscopy. This study investigated the safety of endoscopy in cancer patients receiving AAs.MethodsThis is a retrospective multicenter study of a consecutive case series of 445 cancer patients undergoing endoscopy within 31 days of administration of AAs at 5 specialized cancer centers between April 2008 and August 2014. Endoscopies were classified into two different categories based on the risk of GI bleeding and perforation: low and high. The primary outcome measures were procedure-related adverse events (AEs) and death within 30 days of endoscopy. The severity of AEs was classified according to the common terminology criteria for adverse events (CTCAE) version 4.0. The incidence of AEs and mortality was calculated using the total number of patients as the denominator.Results445 cancer patients with a mean age of 54 years underwent a total of 545 endoscopies. Median time duration from AAs to endoscopy was 11 days. Of 545 endoscopic procedures, 398 (73%) were low-risk and 147 (27%) were high-risk. There were 3 procedure-related AEs: esophageal perforation (grade 3) two days after an EGD, pancreatitis (grade 5) a day after failed ERCP, and bleeding from the gastrostomy site (grade 1) two days after an EGD. Of 445 patients, 29 (6.5%) died within 30 days of the procedure with no deaths deemed procedure-related. The most common causes of death were terminal cancer (n = 10), hepatic decompensation (n = 5) and sepsis (n = 4).ConclusionIn this retrospective study, the rate of endoscopy-related AEs in patients on AAs appears to be low when performed in specialized cancer centers. However, future prospective studies are needed to confirm this finding.

Devastating surgical complications after aflibercept chemotherapy

Abstract Background The use of a new chemotherapy as adjuvant treatment of colorectal cancer is not free of complications. Monoclonal antibodies are associated with bleeding and intestinal perforations. Objective To report the case of a patient who developed a serious complication after treatment with an antiangiogenic drug for colorectal neoplasm. Clinical case The case is presented of a 42-year-old male operated on due to subocclusive rectal cancer with metastasis at the time of diagnosis. Sixteen months after surgery during second-line adjuvant therapy, an intestinal perforation was observed with haemorrhage and intestinal leak to retroperitoneum and left lower extremity. Despite intensive medical and surgical treatment this complication had fatal consequences. Conclusions Future research should be directed at obtaining biomarkers for the specific use of antiangiogenic agents in order to decrease the rate of adverse factors.

Exploring the Benefit/Risk Associated with Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer Patients.

Following the approval of bevacizumab, an antibody targeting VEGF-A, for advanced non-squamous non-small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an anti-VEGFR-1/2/3, platelet-derived growth factor receptor-α/β, fibroblast growth factor receptor-1/2/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union. Many other antiangiogenic agents are being evaluated in phase III trials for NSCLC, including aflibercept, sunitinib, sorafenib, cediranib, and vandetanib. Although many of the same signaling pathways are targeted by these novel agents, mixed efficacy results have been observed in these trials. Moreover, safety issues have raised concerns about using antiangiogenic agents in this patient population, and fatal bleeding events have been reported. Importantly, although no biomarker has yet been validated for antiangiogenic agents in NSCLC, biomarkers that show potential include circulating levels of short VEGF-A isoforms, expression of neuropilin-1 and VEGFR-1 in tumors and plasma, genetic variants in VEGF-A and VEGFR, and tumor protein p53 mutations (with the latter having been shown to correlate with increased levels of VEGF-A transcripts). This review provides an overview of the clinical benefit and risk associated with the use of antiangiogenic agents for NSCLC, and summarizes the research to date on the identification of predictive biomarkers for antiangiogenic therapies. Clin Cancer Res; 23(5); 1137-48. ©2016 AACR.

Early tumour shrinkage as a survival predictor in patients with recurrent glioblastoma treated with bevacizumab in the AVAREG randomized phase II study.

BACKGROUNDDisease assessment for recurrent glioblastoma (GBM) represents a challenge, especially with the use of antiangiogenic agents. Moreover, validated neuroradiological predictors of outcome are lacking. Recently, the concept of early tumor shrinkage (ETS) has been developed to better assess the ability of treatments in determining a rapid and remarkable tumor response.The aim of the study was to evaluate the role of ETS in predicting survival of GBM patients treated with BEVMETHODSWe examined the radiological data of patients with recurrent GBM treated with bevacizumab (BEV) or fotemustine (FTM) in the randomized phase II AVAREG trial (EudraCT: 2011-001363-46).Radiologic assessments at first disease assessment (day 46) were used to calculate the relative change in the sum of the products of perpendicular diameters of all measurable lesions determined by either T1 contrast and T2/FLAIR.RESULTSIn patients treated with BEV, the best ETS cut-off was reduction of 15% with T1 contrast and of 40% with T2/FLAIR. Adopting this cut-off for T1 contrast radiological changes, ETS was a significant predictor of OS for patients treated with BEV (HR = 0.511, 95%CI:0.269-0.971, p = 0.040). The cut-off obtained for T2/FLAIR was not significantly correlated with OS (p = 0.102), but we found a trend for correlation with survival when considering the variable as continuous (p = 0.058).CONCLUSIONSETS evaluating T1 contrast reduction is a helpful predictor of survival in patients with recurrent GBM treated with BEV, and if validated in a larger prospective trial could be a helpful surrogate endpoint.

Intravitreal Antiangiogenic Therapy of Uveitic Macular Edema: A Review.

Uveitic (or inflammatory) macular edema (UME) is one of the most common cause of visual impairment in patients with uveitis and the most frequent structural complication of uveitis. The use of antiangiogenic agents in the management of macular edema due to inflammation is a fairly new approach. It is not entirely clear if these agents should be used as an adjunct to anti-inflammatory therapy or if they can be used as stand-alone agents in edema due to infections where immunosuppressive therapy could be detrimental to the resolution of infection. This treatment paradigm is largely borrowed from large randomized trials in other retinovascular diseases. Similar prospective studies are needed to clarify the role of antiangiogenic therapy in UME.

Abstract IA01: Reengineering the tumor microenvironment to improve cancer treatment: Bench to bedside

Abstract For more nearly four decades, our research has focused on one challenge: improving the delivery and efficacy of anti-cancer therapies. Working on the hypothesis that the abnormal tumor microenvironment fuels tumor progression and treatment resistance, we developed an array of novel imaging technologies and animal models as well as mathematical models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells and the extracellular matrix associated with tumors are abnormal, which together create a hostile biochemical and physical tumor microenvironment (e.g., hypoxia, high interstitial fluid pressure, high solid stress). Our work also revealed how these abnormalities fuel malignant properties of a tumor while preventing treatments from effectively reaching and/or killing cancer cells. We next hypothesized that if we could reengineer the tumor microenvironment, we should be able to improve the treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents—originally designed to starve tumors—could transiently “normalize” tumor vasculature, alleviate hypoxia, increase delivery of drugs and anti-tumor immune cells, and improve the outcome of radiation, chemotherapy and immunotherapy in a number of animal models (Science 2005; Cancer Cell 2014). Moreover, our trials of antiangiogenics in newly diagnosed and recurrent brain tumor (glioblastoma) patients supported this concept. They revealed that the patients whose tumor blood perfusion/oxygenation increased in response to cediranib—a pan-VEGFR tyrosine kinase inhibitor—survived 6-9 months longer than those whose blood perfusion/oxygenation did not increase. The normalization hypothesis also explained how anti-VEGF agents could improve vision in patients with wet age-related macular degeneration, and opened doors to treating other non-malignant diseases harboring abnormal vasculature that afflict more than 500 million people worldwide. These include patients with benign tumors around their nerves—known as vestibular schwannomas (associated with a genetic mutation called neurofibromatosis 2 (NF2)). These patients lose their hearing and there is no medical treatment for them. In collaboration with the clinicians at his MGH, we showed that bevacizumab (Avastin) can normalize the blood vessels and reverse hearing loss in these patients (New England J Medicine 2009). This finding formed the basis of approval of Avastin in UK for this patient population and is currently being evaluated in multiple clinical trials in US (Journal of Clinical Oncology 2016). In parallel, by imaging collagen and measuring perfusion in tumors in vivo, we discovered that the extracellular matrix compresses blood vessels and impedes drug delivery in desmoplastic tumors (e.g., pancreatic cancer, hepatocellular carcinoma, certain breast cancers). We subsequently discovered that widely prescribed angiotensin blockers to control hypertension are capable of “normalizing” the extracellular matrix, opening compressed tumor vessels, and improving the delivery and efficacy of molecular and nanomedicine (Nature Comm 2013). Since approximately 25% of human tumors are fibrotic, and even more in obese patients, our finding offers new hope for improving treatment of highly fibrotic tumors and has led to a clinical trial at MGH on losartan with chemo- and radiation therapy in pancreatic ductal adenocarcinomas (NCT01821729). Finally, we are leveraging our insight into the treatment of adult solid tumors to improve the treatment of the most common solid malignancies of childhood that have limited therapeutic options. For example, the standard treatment for medulloblastoma, the most prevalent pediatric brain tumor, is surgery followed by chemo-radiation. Although potentially curative, treatment often leads to devastating treatment-induced morbidities, including severe cognitive impairment and socio-psychological problems. Moreover, a significant fraction of patients experience disease relapse, and there are virtually no therapeutic options for recurrent disease. We discovered a new target in the microenvironment of pediatric medulloblastomas: placental growth factor (PlGF)—that is expressed across all molecular subtypes of these tumors. PlGF is a member of VEGF-family, but unlike VEGF, PlGF is not required for growth of normal blood vessels. Therefore, in 2007, we proposed that targeting PlGF would be safer in children compared to VEGF (Cell 2007). In 2013, we demonstrated that indeed targeting PlGF blocks medulloblastoma growth and spread, and prolongs survival of mice with these tumors—without causing significant side effects (Cell 2013). We also found that the pediatric patients that express high levels of Neuropilin 1—a receptor of PlGF—in their tumors have a poor prognosis. This finding has led to a phase I/II clinical trial in pediatric brain tumor patients this year using an anti-PlGF antibody (TB-403) (NCT02748135).

Implications of vessel co-option in sorafenib-resistant hepatocellular carcinoma.

The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma (HCC) where alternate therapies are lacking. We recently published a paper entitled “Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma” in the Journal of the National Cancer Institute, providing a potential explanation for this limited benefit. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vasculature by becoming more invasive. Accumulating evidence suggests that many human tumor types may use vessel co-option, which has profound implications for the use of anti-angiogenic agents for cancer treatment.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact

BackgroundPre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and β, RET, KIT). Patients and methodsPatients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). ResultsThirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6–32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31–69%); DCR was 76% (95% CI: 59–88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients.All the cases showed expression of PDGFRβ in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRβ, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRβ immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). ConclusionsSorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRβ-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

Abstract 3400: An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival of 7%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density, and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting. By analyzing the recently expanded TCGA (The Cancer Genome Atlas) dataset, we report here that an angiogenesis gene signature is present in ∼35% of PDACs and is mostly distinct from an angiogenesis signature present in PNETs. Additionally, principal component analysis (PCA) of the entire or angiogenic PDAC and PNET transcriptomes from TCGA indicates that there are large differences in gene expression between these two tumor types. For example, PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, including members of JAK signaling pathways. Functionally, targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib blocks proliferative cross-talk between human pancreatic cancer cells and human endothelial cells. Tumors from the KRC (oncogenic Kras, deleted Rb1) PDAC mouse model show superior enrichment and differential expression of the angiogenic gene signature compared to tumors from the KPC (oncogenic Kras, mutated Trp53) PDAC mouse model. Moreover, treatment of KRC and KPC mice with ruxolitinib suppresses murine PDAC progression in KRC mice but not in KPC mice. These findings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature should be explored in the clinic and that this could lead to improved responses to anti-angiogenic therapy in PDAC. Citation Format: Kelly E. Craven, Jesse Gore, Julie L. Wilson, Murray Korc. An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3400.

Targeted therapy for localized non-small-cell lung cancer: a review.

Targeted therapies have markedly improved the management of patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy in localized NSCLC is less well established. The aim of this review is to analyze trials of targeted therapies in localized NSCLC. In patients with wild-type EGFR, tyrosine kinase inhibitors have shown no efficacy in Phase III trials. Few data are available for EGFR-mutated localized NSCLC, as routine biological profiling is not recommended. Available studies are small, often retrospectives, and/or conducted in a single-center making it difficult to draw firm conclusions. Ongoing prospective Phase III trials are comparing adjuvant tyrosine kinase inhibitor administration versus adjuvant chemotherapy. By analogy with the indication of bevacizumab in advanced NSCLC, use of antiangiogenic agents in the perioperative setting is currently restricted to nonsquamous NSCLC. Several trials of adjuvant or neoadjuvant bevacizumab are planned or ongoing, but for the moment there is no evidence of efficacy. Data on perioperative use of biomarkers in early-stage NSCLC come mainly from small, retrospective, uncontrolled studies. Assessment of customized adjuvant or neoadjuvant therapy in localized NSCLC (with or without oncogenic driver mutations) is a major challenge.

La résistance aux traitements antiangiogéniques

Although the use of anti-angiogenic agents has been considered a promising strategy to block tumor growth and improve the bioavailability of drugs into the tumor, the use of most of them in clinical trials is limited. The development of resistance to some anti-angiogenic agents and their high toxicity are currently under investigations. However, the approach is still valid since this therapeutic tool has lengthened survival of patients with colon, breast, kidney, lungs and liver cancers. The identification of biomarkers in response to this family of drugs is an important area of investigation.

Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction.

Hypoxia is an important contributor to the heterogeneity of the microenvironment of solid tumors and is a significant environmental stressor that drives adaptations which are essential for the survival and metastatic capabilities of tumor cells. Critical adaptive mechanisms include altered metabolism, pH regulation, epithelial-mesenchymal transition, angiogenesis, migration/invasion, diminished response to immune cells and resistance to chemotherapy and radiation therapy. In particular, pH regulation by hypoxic tumor cells, through the modulation of cell surface molecules such as extracellular carbonic anhydrases (CAIX and CAXII) and monocarboxylate transporters (MCT-1 and MCT-4) functions to increase cancer cell survival and enhance cell invasion while also contributing to immune evasion. Indeed, CAIX is a vital regulator of hypoxia mediated tumor progression, and targeted inhibition of its function results in reduced tumor growth, metastasis, and cancer stem cell function. However, the integrated contributions of the repertoire of hypoxia-induced effectors of pH regulation for tumor survival and invasion remain to be fully explored and exploited as therapeutic avenues. For example, the clinical use of anti-angiogenic agents has identified a conundrum whereby this treatment increases hypoxia and cancer stem cell components of tumors, and accelerates metastasis. Furthermore, hypoxia results in the infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and Tumor Associated Macrophages (TAMs), and also stimulates the expression of PD-L1 on tumor cells, which collectively suppress T-cell mediated tumor cell killing. Therefore, combinatorial targeting of angiogenesis, the immune system and pH regulation in the context of hypoxia may lead to more effective strategies for curbing tumor progression and therapeutic resistance, thereby increasing therapeutic efficacy and leading to more effective strategies for the treatment of patients with aggressive cancer.

VEGF inhibitors in glaucoma surgery

Vascular endothelial growth factor (VEGF) is a signaling protein, that controls vasculogenesis, angiogenesis, vascular support and stimulates permeability of small blood vessels. The following isoforms are presently known: VEGF-A, VEGF-B, VEGF-C, VEGF-В and PGF. VEGF-A, that regulates neoangiogenesis and fibroblast formation, is thought to play the most important role in human organism. Increased expression of VEGF may lead to development and aggravation of pathological conditions including oncology. The article presents a review of preclinical and clinical studies of the main VEGF-inhibitors - bevacizumab and ranibizumab, as well as a brief account on other existing medications of this group. It describes ophthalmological indications for the use of antiangiogenetic agents, as well as the ways of their possible off-label use. The review presents investigations of intravitreal and intracameral injections of VEGF-inhibitors in patients with retinal, chorioidal, iris, and anterior chamber angle neovascularization. It gives examples of successful anti-VEGF use before Ahmed glaucoma valve drainage device implantation and in cases of neovascular glaucoma, induced by radiation therapy for intraocular tumors. Tenon’s capsule’s fibroblasts take part in the process of postoperative wound healing and scarring. According to the latest research, this process could be modulated by angiogenesis inhibitors. This review also recounts the use of anti-angiogenic agents to inhibit postoperative fibroblast proliferation, when used as monotherapy, or as an adjuvant to mitomycin С or 5-fluorouracil. It reviews the research on VEGF-inibitors use in combination with postoperative needling.

Preoperative biomarkers of tumour vascularity are elevated in patients with glioblastoma multiforme

We investigated the correlation between the circulating and imaging biomarkers of tumour vascularity, and examined whether they are prognostic of outcomes in patients with glioblastoma multiforme (GBM). Despite the increasing use of anti-angiogenic agents within neuro-oncology, there are still no validated biomarkers to monitor for a treatment response or relapse. The pre- and postoperative circulating endothelial cell (CEC) and progenitor cell (CEP) levels were assessed. Preoperative perfusion-weighted MRI (PWI) was also performed, and the relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing tumour were analysed. A novel PWI parameter (rCBVload) was developed to estimate the total volume of perfused tumour vessels, and it was hypothesised that this parameter would correlate with CEC and CEP concentrations. In total, 24 GBM patients were included. The mean preoperative CEC concentration was significantly higher in GBM patients than the controls (p=0.019), and it then declined significantly postoperatively (p=0.009). The preoperative CEP levels were significantly correlated with the median tumour rCBV (Spearman rank-order coefficient=0.526; p=0.039). Neither CEC nor CEP was correlated with the total tumour vessel volume, as measured by rCBVload. None of the biomarkers that were investigated showed a significant correlation with progression-free or overall survival. We conclude that CEC are potentially useful biomarkers to monitor GBM patients during treatment. We found that CEC are increased in the presence of GBM, and that CEP levels appear to be proportional to tumour vascularity, as measured on PWI. However, in this study, none of the biomarkers of GBM vascularity were highly prognostic of patient outcomes.

Biomarkers of Angiogenesis in Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 10% of all new cancer diagnoses. Angiogenesis is a tightly regulated process that is mediated by a group of angiogenic factors such as vascular endothelial growth factor and its receptors. Given the widespread use of antiangiogenic agents in CRC, there has been considerable interest in the development of methods to identify novel markers that can predict outcome in the treatment of this disease with angiogenesis inhibitors. Multiple biomarkers are in various phases of development and include tissue, serum, and imaging biomarkers. The complexity of the angiogenesis pathway and the overlap between the various angiogenic factors present a significant challenge to biomarker discovery. In our review, we discuss the angiogenesis pathway and the most promising evolving concepts in biomarker discovery, as well as highlight the landmark studies that identify subgroups of patients with CRC who may preferentially benefit from angiogenesis inhibitors.

Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers.

In ovarian cancer (OC), the best established anti-angiogenic drug, bevacizumab, has demonstrated only modest prolonged progression free survival (PFS) and no increased overall survival (OS). The unanswered question is in which clinical situation bevacizumab might benefit ovarian cancer patients most. The cost-benefit analysis in the primary treatment was found not to be favorable but the use in the recurrent OC setting might be more compelling. Multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKI) such as cediranib and pazopanib have shown some therapeutic benefits with improvements of PFS and OS in patients with platinum-sensitive as well as resistant OC, in whom there is a major need for novel therapies. Very promising is also the observed improvement of PFS in recurrent OC in patients when combining cediranib with the PARP inhibitor olaparib without giving additional chemotherapy. The anti-angiogenic agent trebananib has achieved similar results like TKI, but has a favorable toxicity profile which does not overlap with those of VEGF inhibitors. In cervical cancer the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic chemotherapy-naive disease results in a significant increase in OS. Considering the lack of therapeutic options in this difficult clinical setting, the inclusion of bevacizumab most likely will become a new standard for recurrent cervical cancer. In uterine sarcomas as very aggressive malignancies with a substantial need for better therapies the observed improved PFS with sorafenib warrants further investigation. No data showing a convincing improvement of survival in endometrial cancer have been presented yet. In view of the limited PFS and OS benefit observed with anti-angiogenics in gynecologic oncology, increased morbidity due to side effects of this treatment resulting in loss of quality of life and also substantial costs have to be taken into consideration. Thorough case selection based on molecular subgrouping of gynecologic cancers will therefore be a prerequisite for future anti-angiogenic therapy. This will require the integration of molecular diagnostics which still have to be developed and standardized.

Interception of host angiogenic signalling limits mycobacterial growth.

Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis1,2. Here we examine the development and consequences of vascularisation of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model characterised by organised granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis2. Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule VEGFA. Pharmacological inhibition of the VEGF pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergise with the first-line anti-tubercular antibiotic rifampicin as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations3. Our data suggest that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting TB therapy, particularly in extensively drug-resistant disease where current antibiotic regimens are largely ineffective.

Antiangiogenic Agents Combined with Chemotherapy in the First-Line Treatment of Advanced Non-Small-Cell Lung Cancer: Overall and Histology Subgroup-Specific Meta-Analysis

Aim: This study investigated the overall and histology subtype-specific results of antiangiogenic agents combined with chemotherapy versus chemotherapy alone for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Methods: Literature retrieval, trial selection, data collection, and statistical analysis were performed according to the Cochrane Handbook. The outcome measures were tumor response rate, progression-free survival (PFS), overall survival (OS), and adverse effects. Results: 13 randomized controlled trials comprising 5,451 patients were included. The meta-analysis showed a higher response rate (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.53-0.74) and a significantly prolonged PFS (hazard ratio (HR) 0.75, 95% CI 0.66-0.85) and OS (HR 0.92, 95% CI 0.86-0.98) in the groups combining antiangiogenic agents with chemotherapy versus the chemotherapy alone groups. In the histology subgroup analysis, treatment with antiangiogenic agents plus chemotherapy significantly improved the RR, PFS, and OS as compared with the chemotherapy groups in patients with nonsquamous NSCLC, but not in those with squamous NSCLC. The risk of grade 3/4 thrombocytopenia, hypertension, bleeding, proteinuria, rash, diarrhea, fatigue, headache, anorexia, and febrile neutropenia was significantly increased in the antiangiogenic agent combination groups as compared with the chemotherapy groups. Conclusion: The use of antiangiogenic agents in addition to chemotherapy is a valid option for the first-line treatment of advanced NSCLC. The benefit is restricted to patients with nonsquamous-cell tumors.

Antiangiogenic therapy for high-grade glioma.

The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high-grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma (GBM) and carries a median survival in treated patients of about 15 months. GBMs are rich in blood vessels (i.e. highly vascular) and in a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation (the process of angiogenesis). Antiangiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several antiangiogenic agents have been investigated in clinical trials in newly diagnosed and recurrent HGG, showing promising preliminary results. This review was undertaken to report on the benefits and harms associated with the use of antiangiogenic agents in the treatment of HGGs. To evaluate the efficacy and toxicity of antiangiogenic therapy in patients with high-grade glioma. This intervention can be used in two broad groups of patients: those with first diagnosis as part of 'adjuvant' therapy, and those with recurrent or progressive disease. Comparisons will include the following.• Treatment with antiangiogenic therapy versus placebo.• Treatment (such as chemotherapy or chemoradiotherapy) with antiangiogenic therapy added versus the same treatment without the addition of antiangiogenic therapy. Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2014; MEDLINE to April 2014 and EMBASE to April 2014. Proceedings of relevant oncology conferences since 2000 were handsearched. RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG. Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. After a comprehensive literature search, seven eligible RCTs were identified (total of 2987 participants). Significant design heterogeneity was noted in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to GBMs, and no eligible studies evaluated other HGGs. Four studies were available only in abstract form. We have reserved an overall assessment of the quality of the evidence until the final study publications are received. The three studies that have been published in full were judged to have low risk of bias. The seven trials of 2987 participants included in this systematic review did not show improvement in OS with the addition of antiangiogenic therapy (pooled hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86 to 1.02; P value 0.16). However, pooled analysis of PFS from six studies (2847 participants) showed improvement in PFS with the addition of antiangiogenic therapy (HR 0.74, 95% CI 0.68 to 0.81; P value < 0.00001). Bevacizumab was the antiangiogenic therapy more likely to yield favourable results. Pooled HR for PFS for bevacizumab studies (three studies with 1712 participants) was significant at 0.66 (95% CI 0.59 to 0.74; P value < 0.00001), and this was reflected in the lower hazard ratio reported in the pooled analysis of bevacizumab studies compared with the overall analysis. Nevertheless, this finding was not significant for OS (HR 0.92, 95% CI 0.83 to 1.02; P value 0.12). Similar to trials of antiangiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing and the potential for thromboembolic events, although generally, the occurrence of grade 3 events of this kind was low (< 14.1%), consistent with reported findings of studies of bevacizumab in other tumours. In patients with newly diagnosed GBM, the use of antiangiogenic therapy does not improve survival, despite evidence of improved progression-free survival. Thus at this time, evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival.Bevacizumab may confer a progression-free survival benefit in GBM; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient.Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM, the impact of this on quality of life remains unclear.Adequately powered, randomised, placebo-controlled studies of bevacizumab in recurrent GBM (or HGG) are needed.Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high-grade glioma histologies.

VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation

In ischemic disorders such as chronic wounds and myocardial ischemia, there is inadequate tissue perfusion due to vascular insufficiency. Besides, it has been observed that prolonged use of anti-angiogenic agents in cancer therapy produces cardiovascular toxicity caused by impaired vessel integrity and regeneration. In the present study, we used VEGFR tyrosine kinase inhibitor II (VRI) to chemically induce vascular insufficiency in zebrafish in vivo and human umbilical vein endothelial cells (HUVEC) in vitro to further study the mechanisms of vascular morphogenesis in these pathological conditions. We also explored the possibility of treating vascular insufficiency by enhancing vascular regeneration and repair with pharmacological intervention. We observed that pretreatment of VRI induced blood vessel loss in developing zebrafish by inhibiting angiogenesis and increasing endothelial cell apoptosis, accompanied by down-regulation of kdr, kdrl and flt-1 genes expression. The VRI-induced blood vessel loss in zebrafish could be restored by post-treatment of calycosin, a cardiovascular protective isoflavone. Similarly, VRI induced cytotoxicity and apoptosis in HUVEC which could be rescued by calycosin post-treatment. Further investigation of the underlying mechanisms showed that the PI3K/AKT/Bad cell survival pathway was a main contributor of the vascular regenerative effect of calycosin. These findings indicated that the cardiovascular toxicity in anti-angiogenic therapy was mainly caused by insufficient endothelial cell survival, suggesting its essential role in vascular integrity, repair and regeneration. In addition, we showed that VRI-induced blood vessel loss in zebrafish represented a simple and effective in vivo model for studying vascular insufficiency and evaluating cancer drug vascular toxicities.