Bronchial washing levels of vascular endothelial growth factor receptor-2 (VEGFR2) correlate with overall survival in NSCLC patients

The aim of this study was to define pre-treatment VEGF, VEGFR1 and VEGFR2 levels in serum and bronchial washing samples of NSCLC patients in order to examine their correlation to survival. Forty patients with histologically confirmed NSCLC were enrolled. The results indicated that circulating VEGF was correlated to T-classification, as were the ratios of VEGF/VEGFR2 in serum and washing. Best chemotherapy response was observed at lower serum and washing VEGF concentrations. Higher VEGF levels in washing were associated with worse overall survival and progression-free survival. Similar were the results at high values of VEGF/VEGFR2 ratio in washing. Multivariate analysis revealed VEGFR2 levels in serum and washing as independent markers for overall survival. In conclusion, washing VEGFR2 levels are correlated to overall survival, whereas serum and washing VEGF levels are predictive of chemotherapy response. These could help recognize NSCLC patients who benefit from an aggressive therapeutic approach.     

Fighting fire with fire: poisonous Chinese herbal medicine for cancer therapy

Ethnopharmacological relevance

Following the known principle of “fighting fire with fire”, poisonous Chinese herbal medicine (PCHM) has been historically used in cancer therapies by skilled Chinese practitioners for thousands of years. In fact, most of the marketed natural anti-cancer compounds (e.g., camptothecin derivatives, vinca alkaloids, etc.) are often known in traditional Chinese medicine (TCM) and recorded as poisonous herbs as well. Inspired by the encouraging precedents, significant researches into the potential of novel anticancer drugs from other PCHM-derived natural products have been ongoing for several years and PCHM is increasingly being recognized as a gathering place for promising anti-cancer drugs. The present review aimed at giving a rational understanding of the toxicity of PCHM and, especially, providing the most recent developments on PCHM-derived anti-cancer compounds.

Materials and methods

Information on the toxicity and safety control of PCHM, as well as PCHM-derived anti-cancer compounds, was gathered from the articles, books and monographs published in the past 20 years.

Results

Based on an objective introduction to the CHM toxicity, we clarified the general misconceptions about the safety of CHM and summarized the traditional experiences in dealing with the toxicity. Several PCHM-derived compounds, namely gambogic acid, triptolide, arsenic trioxide, and cantharidin, were selected as representatives, and their traditional usage and mechanism of anti-cancer actions were discussed.

Conclusions

Natural products derived from PCHM are of extreme importance in devising new drugs and providing unique ideas for the war against cancer. To fully exploit the potential of PCHM in cancer therapy, more attentions are advocated to be focused on their safety evaluation and mechanism exploration.     

The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway

Development of a novel type of angiogenesis inhibitor will be essential for further improvement of therapeutics against cancer patients. We examined whether an octahydronaphthalene derivative, AMF-26, which was screened as an inhibitor of intercellular adhesion molecule-1 (ICAM-1) production stimulated by inflammatory stimuli in vascular endothelial cells, could block angiogenesis in response to vascular endothelial growth factor (VEGF) and/or inflammatory cytokines. Low dose AMF-26 effectively inhibited the tumor necrosis factor-α (TNF-α)- or the interleukin-1β (IL-1β)-induced production of ICAM-1 in human umbilical vascular endothelial cells (HUVECs). We found that the TNF-α-induced phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear translocation of p65 were impaired by AMF-26 in both endothelial cells and cancer cells. AMF-26 was found to inhibit the phosphorylation of VEGF receptor 1 (VEGFR1), VEGFR2 and the downstream signaling molecules Akt, extracellular signal-regulated kinase (ERK)1/2 stimulated by VEGF in HUVECs. Therefore, the VEGF-induced proliferation, migration and tube formation of vascular endothelial cells was highly susceptible to inhibition by AMF-26. Oral administration of AMF-26 significantly blocked VEGF- or IL-1β-induced angiogenesis in the mouse cornea, and also tumor angiogenesis and growth. Together, our results indicate that AMF-26 inhibits angiogenesis through suppression of both VEGFR1/2 and nuclear factor-κB (NF-κB) signaling pathways when stimulated by VEGF or inflammatory cytokines. AMF-26 could be a promising novel candidate drug for cancer treatments.     

A preclinical and clinical review of aflibercept for the management of cancer

Aflibercept, also known as vascular endothelial growth factor (VEGF)-Trap, is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting not only all forms of VEGF-A, but also VEGF-B and placental growth factor. It inhibits VEGF-induced angiogenesis in preclinical models. In tumor models, aflibercept is associated with the reduction of tumor vasculature and size, and the inhibition of ascites formation. Clinical studies are investigating the use of aflibercept alone and in combination with other antineoplastic therapies for the treatment of various cancers. Phase I and II studies have provided proof of principle, and support the continuing clinical investigation of aflibercept. Results from the phase III study, VITAL, of aflibercept in the second-line setting in patients with advanced non-small cell lung cancer [NCT00532155] demonstrated efficacy in progression-free survival and overall objective response rate, but overall survival was not significantly improved. A full report awaits publication. The Phase III VANILLA trial in metastatic pancreatic cancer [NCT00574275] showed no improvement in overall survival. Most recently, the phase III VELOUR study [NCT00561470] of aflibercept plus FOLFIRI compared with placebo plus FOLFIRI in patients with metastatic colorectal cancer following failure of an oxaliplatin regimen showed significant improvements in overall survival, progression-free survival, and response rate and the complete results have been submitted to a peer-reviewed journal. This review summarizes preclinical and clinical data for aflibercept and discusses future directions and clinical trials for this agent.     

EGFR、VEGFR1/Flt-1在未放疗和放疗后食管鳞癌组织中的表达

目的：探讨食管鳞癌组织中内皮生长因子受体（EGFR）、血管内皮生长因子受体1（VEGFR1/Flt-1）的表达与术前辅助放疗敏感性的关系。方法：采用免疫组织化学染色方法（EnVision二步法）检测40例未接受放疗和40例接受放疗后手术切除的食管鳞癌组织,以及20例切除组织的上切缘正常组织中EGFR、VEGFR1/Flt-1的表达。结果：EGFR在正常组织中无表达,在未接受放疗食管鳞癌中的表达率为77.5%,在接受放疗后食管鳞癌中的表达率为70%,EGFR在放疗后食管鳞癌中的表达与未放疗食鳞癌的表达相比,经卡方检验其差异具有统计学意义（P〈0.05）。VEGFR1/Flt-1在正常组织中阳性表达率为80%,在未接受放疗食管鳞癌中的表达率为62.5%,在接受放疗后食管鳞癌中的表达率为80%,VEGFR1/Flt-1在放疗后食管鳞癌中的表达与未放疗食管鳞癌的表达相比较,经卡方检验其差异具有统计学意义（P〈0.05）。结论：检测EGFR、VEGFR1/Flt-1有助于预测食管鳞癌术前放疗的疗效。     

Molecular targeting of VEGF/VEGFR signaling by the anti-VEGF monoclonal antibody BD0801 inhibits the growth and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths with 750,000 newly diagnosed cases each year. Surgery, radiotherapy, and chemotherapy constitute the main treatment modalities for HCC, but liver cirrhosis and damage often occur. Molecular targeted drugs have been recently developed to treat HCC. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) autocrine signaling is closely related to the growth, progression, and metastasis of HCC, making the VEGF/VEGFR axis an ideal target for the development of molecular targeted agents. Here, we report the effects of the novel anti-VEGF humanized monoclonal antibody BD0801 on the growth of HCC cells in vitro and in vivo as well as the underlying mechanisms. BD0801 significantly inhibited the proliferation of HepG2, SMMC-7721, and Bel7402 cells in vitro, accompanied with an induction of apoptosis and cell cycle arrest at the G1 phase. BD0801 potently suppressed AKT, Erk1/2, and retinoblastoma (Rb) phosphorylation, while increasing p21 and decreasing cyclin D1 protein levels. BD0801 significantly inhibited growth in mouse tumor xenografts and induced cell apoptosis of HepG2 and SMMC-7721 tumor xenografts. Furthermore, BD0801 effectively reduced the vascular density and tumor tissue microvessel density (MVD). Similarly, BD0801 decreased AKT, Erk1/2, and Rb phosphorylation and cyclin D1 expression whereas it increased p21 protein expression in mouse HCC tumor xenografts. Importantly, BD0801 showed a better effect than Bevacizumab (Bev) on the inhibition of cell growth and induction of apoptosis in HCC cells in vitro and in vivo. These findings suggest that BD0801 is a potent anti-VEGF monoclonal antibody for the treatment of HCC.     

儿童急性白血病骨髓细胞中血管内皮生长因子及其受体的表达

  目的 探讨血管内皮生长因子（VEGF）及其受体（VEGFR）在儿童急性白血病（AL）患者骨髓中的表达,分析其在化疗前后的变化。方法 采用免疫组化S-P法检测53例AL患儿治疗前后以及对照组骨髓中VEGF／VEGFR（包括Flt-1和KDR两种）变化,分析其与临床特征的关系。结果 VEGF,Flt-1,KDR在AL患儿骨髓中表达水平高于对照组。VEGF,Flt-1,KDR的表达于化疗达完全缓解（CR）后下调;化疗后未获得CR患儿VEGF,Flt-1,KDR的表达在化疗前后差异无统计学意义。骨髓中VEGF,Flt-1,KDR的表达水平在不同年龄、性别、有无髓外浸润间差异无统计学意义。结论 VEGF,Flt-1,KDR在儿童AL中呈高表达,化疗后表达明显降低,说明VEGF可能作为评价儿童AL化疗反应的指标。     

Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma

BACKGROUND:

The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial.

METHODS:

Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression‐free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed.

RESULTS:

Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child‐Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression‐free rate at 16 weeks was 31.8% (34.2% for patients with Child‐Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child‐Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child‐Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child‐Pugh class A hepatic function). The most common linifanib‐related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib‐related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome.

CONCLUSIONS:

Single‐agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 American Cancer Society.     

VEGF-C和受体Flt-4mRNA在舌鳞癌中的表达及临床意义

目的　研究舌鳞状细胞癌组织中血管内皮生长因子C(vascularendothelialgrowthfactorC ,VEGF C)及其受体VEGFR 3(flt 4 )的表达情况 ,分析其在淋巴转移中的作用。方法　采用RT PCR法分析 2 2例新鲜标本VEGF C/flt 4mRNA的表达情况 ,并统计分析其与各临床病理特点之间的关系。结果　 2 2例中 1 6例VEGF CmRNA表达阳性 ,其中 1 2例flt 4mRNA阳性 ,VEGF C和flt 4mRNA的表达高度一致 (P <0 .0 1 )。舌鳞癌VEGF C明显高于正常组织和良性病变 ;和肿瘤病理分级、肿瘤颈淋巴结转移显著相关 ,和肿瘤发病年龄、性别以及肿瘤T分期无相关性。结论　VEGF C/flt4在舌癌表达高于正常组织和良性病变 ;与肿瘤的预后密切相关。在肿瘤淋巴转移中起重要作用     

Emerging therapeutics in refractory renal cell carcinoma

Introduction: Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies (‘refractory’ mRCC). Recently approved agents in this space have shown great promise.

Areas covered: This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.

Expert opinion: Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.