Anti-angiogenesis Agents Research Articles

New Developments in Anti-Angiogenic Therapy of Cancer, Review and Update.

Angiogenesis is one of the critical physiological processes, by which the new blood vessels are generated from the pre-existing vessels in the early stage of vasculogenesis. While normal angiogenesis is critical for development and tissue growth, pathologic angiogenesis is important for the growth and spread of cancers by supplying nutrients and oxygen as well as providing a conduit for distant metastasis. In the last two decades, angiogenesis has been the area of extensive researches, indicating antiangiogenic target therapy as an effective strategy for cancer therapy. At present, this field has become a major avenue for research and development of novel therapeutics. This review is dedicated to an updated review of the most prominent antiangiogenic agents, emphasizing the novel advancements and their applications, in particular, in the fields of antibodies, peptides, vaccines, endogenous inhibitors, Nanoparticles (NPs), antiangiogenic oligonucleotides and small molecules. Also, the potential role of 3D microfluidic models as an affordable and time-saving tool for angiogenesis investigations are discussed. Firstly, we collected and summarized new developments that have occurred in all review and research articles in databases. Then, we used important keywords related to antiangiogenic target therapy and their applications for retrieval of most relevant data. This review is based on recent research and review articles and intended to cover all newly discovered agents inhibiting tumor angiogenesis and in particular, VEGF. New research studies have shown that anti-angiogenesis agents especially, in the form of combination therapy are effective in various cancers treatment.

Abstract 4244: The efficacy and safety of anti-PD-1 therapy in metastatic sarcomas

Abstract Sarcomas are a group of rare and malignant tumors originating from mesenchymal tissue with a variety of cellular subtypes. Although several major standard treatments, including neo-adjuvant and adjuvant chemotherapy, surgery and radiation, have made breakthroughs to improve overall survival, there are few additional effective treatments for metastatic sarcomas that have failed traditional therapy. With the encouraging efficacy of PD-1 monoclonal antibodies in nonresectable or metastatic malignant melanomas and lung cancers, immunosuppressive agents provide new hope for the treatment of sarcomas. We retrospectively collected information from 15 patients with stage IV sarcomas who were treated with a PD-1 inhibitor with or without angiogenesis inhibitor after the failure of traditional treatments, from June 15, 2016 to September 30, 2019. The primary observation endpoint was median progression-free survival (mPFS), and the objective response rate (ORR) and the disease control rate (DCR) were secondary endpoints. Treatment-related adverse events (AEs) were evaluated. Patients were observed until death, loss to follow-up, or the end of the PD-1 inhibitor therapy. The average follow-uptime was 8.47 months (1.97-28.12 months). At 12 weeks, the ORR was 23.1% (3/13) and the DCR was 84.6% (11/13). Finally the overall median PFS was 5.06 months, the ORR was 15.4% (2/13) and the DCR was 61.5% (8/13). Common AEs (occurring with 15 patients) included grade 4 hypertension (n=1, 2.6%), grade 3 leukopenia (n=1,2.6%), grade 2 hand and foot syndrome(HFSR) (n=2, 5.1%), grade 1 reactive capillary hyperplasia (RCCEP) (n=7,17.9%), fatigue and weakness (n=5, 12.8%), digestive dysfunction (n=3,7.7%) and fever (n=3,7.7%). The results indicate that PD-1 inhibitors based therapies are effective, safe and well tolerated in patients with advanced sarcomas. The PD-1 inhibitor combined with anti-angiogenesis agents might provide a new and effective strategy to treat metastatic sarcomas. Citation Format: Jilong Yang. The efficacy and safety of anti-PD-1 therapy in metastatic sarcomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4244.

Discovery of novel anti-angiogenesis agents. Part 11: Development of PROTACs based on active molecules with potency of promoting vascular normalization.

Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926cells without significant cytotoxicity against HEK293cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs.

Recent Advances and Impact of Chemotherapeutic and Antiangiogenic Nanoformulations for Combination Cancer Therapy.

Traditional chemotherapy, along with antiangiogenesis drugs (combination cancer therapy), has shown reduced tumor recurrence and improved antitumor effects, as tumor growth and metastasis are often dependent on tumor vascularization. However, the effect of combination chemotherapy, including synergism and additive and even antagonism effects, depends on drug combinations in an optimized ratio. Hence, nanoformulations are ideal, demonstrating a great potential for the combination therapy of chemo-antiangiogenesis for cancer. The rationale for designing various nanocarriers for combination therapy is derived from organic (polymer, lipid), inorganic, or hybrid materials. In particular, hybrid nanocarriers that consist of more than one material construct provide flexibility for different modes of entrapment within the same carrier—e.g., physical adsorption, encapsulation, and chemical conjugation strategies. These multifunctional nanocarriers can thus be used to co-deliver chemo- and antiangiogenesis drugs with tunable drug release at target sites. Hence, this review attempts to survey the most recent advances in nanoformulations and their impact on cancer treatment in a combined regimen—i.e., conventional cytotoxic and antiangiogenesis agents. The mechanisms and site-specific co-delivery strategies are also discussed herein, along with future prospects.

Galectin-3 expression and secretion by tumor-associated macrophages in hypoxia promotes breast cancer progression

Tumor-associated macrophages (TAMs) have been shown to be associated with poor prognosis of cancer and are predominately localized in the hypoxia regions of tumor. We demonstrated in this study that hypoxia increases the synthesis and secretion of galectin-3 by TAMs. The increased expression of galectin-3 in TAMs was seen to be associated with nucleation of transcription factor NF-κB through generation and activation of ROS and promoted tumor growth and metastasis in vitro and in mice through multiple molecular mechanisms. It was found that the TAMs-mediated promotion of tumor growth and metastasis in hypoxia was inhibited by administration of macrophage-depletion agent clodronate liposomal (CL) or galectin-3 inhibitor modified citric pectin (MCP) in orthotopic syngeneic mammary adenocarcinoma model and metastasis model. Co-administration of anti-angiogenesis agent sorafenib or bevacizumab with CL and MCP showed to cause stronger inhibition of tumor growth and metastasis than administration of each agent alone. These results indicate that hypoxia-induced galectin-3 expression and secretion from TAMs promotes tumor growth and metastasis. Targeting the actions of galectin-3 in hypoxia may be a potential therapeutic strategy for cancer treatment.

Snail promotes the generation of vascular endothelium by breast cancer cells

A further understanding of tumor angiogenesis is urgently needed due to the limited therapeutic efficacy of anti-angiogenesis agents. However, the origin of endothelial cells (EC) in tumors remains widely elusive and controversial. Snail has been thoroughly elucidated as a master regulator of the epithelial–mesenchymal transition (EMT), but its role in endothelium generation is not yet established. In this study, we reported a new and unexpected function of Snail in endothelium generation by breast cancer cells. We showed that high Snail-expressing breast cancer cells isolated from patients showed more endothelium generated from these cells. Expression of Snail was positively correlated with endothelial markers in breast cancer patients. The ectopic expression of Snail induced endothelial marker expression, tube formation and DiI-AcLDL uptake of breast cancer cells in vitro, and enhanced tumor growth and microvessel density in vivo. Snail-mediated endothelium generation depended on VEGF and Sox2. Mechanistically, Snail promoted the expression of VEGF and Sox2 through recruiting the p300 activator complex to these promoters. We showed the dual function of Snail in tumor initiation and angiogenesis in vivo and in vitro through activation of Sox2 and VEGF, suggesting Snail may be an ideal target for cancer therapy.

Oridonin exhibits anti-angiogenic activity in human umbilical vein endothelial cells by inhibiting VEGF-induced VEGFR-2 signaling pathway

Oridonin has been found to be a potential anti-angiogenesis agent. However, its functional targets and the underlying mechanisms are still vague. In vitro studies we found that oridonin not only inhibited VEGF-induced cell proliferation, migration and tube formation but also caused G2/M phase arrest and triggered cellular apoptosis in HUVECs. In mechanistic studies revealed that oridonin exhibited the anti-angiogenic potency, at least in part, through the down-regulation of VEGFR2-mediated FAK/MMPs, mTOR/PI3K/Akt and ERK/p38 signaling pathways which led to reduced invasion, migration, and tube formation in HUVECs. Our results could provide evidence that oridonin exerts strong anti-angiogenesis activities via specifically targeting VEGFR2 and its signaling pathway.

Mining the role of angiopoietin-like protein family in gastric cancer and seeking potential therapeutic targets by integrative bioinformatics analysis.

BackgroundThe indistinctive effects of antiangiogenesis agents in gastric cancer (GC) can be attributed to multifaceted gene dysregulation associated with angiogenesis. Angiopoietin‐like (ANGPTL) proteins are secreted proteins regulating angiogenesis. They are also involved in inflammation and metabolism. Emerging evidences have revealed their various roles in carcinogenesis and metastasis development. However, the mRNA expression profiles, prognostic values, and biological functions of ANGPTL proteins in GC are still elucidated.MethodsWe compared the transcriptional expression levels of ANGPTL proteins between GC and normal gastric tissues using ONCOMINE and TCGA‐STAD. The prognostic values were evaluated by LinkedOmics and Kaplan–Meier Plotter, while the association of expression levels with clinicopathological features was generated through cBioPortal. We conducted the functional enrichment analysis with Metascape.ResultsThe expression of ANGPTL1/3/6 was lower in GC tissues than in normal gastric tissues. High expression of ANGPTL1/2/4 was correlated with short overall survival and post‐progression survival in GC patients. Upregulated ANGPTL1/2 was correlated with higher histological grade, non‐intestinal Lauren classification, and advanced T stage, while ANGPTL4 exhibited high expression in early T stage, M1 stage, and non‐intestinal Lauren classification.ConclusionsIntegrative bioinformatics analysis suggests that ANGPTL1/2/4 may be potential therapeutic targets in GC patients. Among them, ANGPTL2 acts as a GC promoter, while ANGPTL1/4’s role in GC is still uncertain.

Pancreatic cancer stroma: an update on therapeutic targeting strategies.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cellswithin the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

First-line combination immunotherapy for metastatic non-small cell lung cancer.

Immunotherapy has recently become an important treatment modality, especially for non-small cell lung cancer (NSCLC) and melanoma patients. Several large-scale phase III trials of first-line treatments for metastatic NSCLC have documented prolonged patient survival, including progression-free survival and overall survival for immune checkpoint inhibitors (ICIs) used alone or in combination with chemotherapy. However, a significant proportion of patients experienced disease progression shortly after starting single-agent ICI treatment even after biomarker selection, such as programmed cell death-ligand 1 and tumor mutation burden. The present review was performed to identify ways to enhance ICI efficacy in the first-line treatment of metastatic NSCLC patients. At least four effective ways of combination treatment modalities are currently available, namely, immune therapy in combination with radiotherapy, chemotherapy, antiangiogenesis, or other immunotherapeutic agents.

7‑Difluoromethyl‑5,4'‑dimethoxygenistein exerts anti‑angiogenic effects on acute promyelocytic leukemia HL‑60 cells by inhibiting the TLR4/NF‑κB signaling pathway.

Angiogenesis plays an important role in the development and metastasis of tumors, and anti-angiogenesis agents are used to treat tumors. For example, the acute promyelocytic leukemia (APL) may be treated with arsenic trioxide. Angiogenesis in APL is a multi-step dynamic equilibrium process coordinated by various angiogenic stimulators and inhibitors, which play key roles in the occurrence, progression and chemosensitivity of this disease. Our research group previously synthesized 7-difluoromethyl-5,4′-dimethoxygenistein (DFMG), and found that it inhibits angiogenesis during atherosclerotic plaque formation. In the present study, the effect and mechanism of DFMG in angiogenesis induced by APL HL-60 cells was investigated using a chick embryo chorioallantoic membrane model and Matrigel tubule formation assays. The results obtained revealed an anti-angiogenesis effect of DFMG towards HL-60 cells. When the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway was inhibited, the anti-angiogenic effect of DFMG was further enhanced. However, when the TLR4/NF-κB signaling pathway was activated, the anti-angiogenic effect of DFMG was attenuated. These results demonstrated that DFMG inhibits angiogenesis induced by APL HL-60 cells, and provides insights into the mechanism by which DFMG inhibits the TLR4/NF-κB signaling pathway. In conclusion, in the present study, the anti-angiogenesis effect of DFMG on APL has been reported, and the mechanism by which DFMG induced the anti-angiogenesis effect was explored. These findings have provided a potential new drug candidate for the treatment of patients with APL.

Abstract A16: A GUCY2c-CD3 bispecific engages T cells to induce cytotoxicity in gastrointestinal tumors

Abstract Background: Guanylyl cyclase C (GUCY2C) is a regulator of intestinal homeostasis and is expressed in more than 90% of colorectal cancer (CRC), as well as in other gastrointestinal malignancies. Target expression in normal tissues is largely restricted to the apical side of intestinal epithelial tight junctions, which could allow for preferential uptake of GUCY2C-targeted biologics by tumors that have disrupted tight junction architecture. Here we demonstrate tumor-selective uptake and potent efficacy with a half-life extended, GUCY2C-CD3 bispecific molecule that recruits CD3-positive T cells to induce cytotoxicity of GUCY2C-expressing tumors in several CRC models in vivo. Additionally, to address immune evasion mechanisms, rational combinations of the bispecific are explored with immune checkpoint blockade agents, as well as by blocking angiogenesis, which has been reported to enhance T-cell infiltration into tumors. Methods: GUCY2C-CD3 mediated activity was evaluated in vivo in several cell line- and patient derived-xenograft models of CRC, using adoptive transfer of human T cells in established subcutaneous and orthotopic tumors. Immunohistochemistry was performed to demonstrate biodistribution of the drug and recruitment of activated T cells in GUCY2C-expressing tumors vs. normal tissues. We also performed CYTOF analyses on GUCY2C-CD3-treated tumors and tumor-infiltrating lymphocytes (TILs) to identify markers of immune evasion. Combination studies with anti PD-1/PD-L1 checkpoint blockade agents and with an anti VEGF-A antibody were performed using the adoptive transfer model. Results: GUCY2C-CD3 bispecific showed preferential biodistribution to GUCY2C-expressing xenograft tumors compared to normal tissue. The drug demonstrated potent dose-dependent efficacy in several CRC models with no signs of toxicity. Bispecific treated tumors not only showed recruitment of activated T cells to the tumor site, but also upregulated checkpoint mechanisms, such as PD-L1 on tumors and exhaustion markers on TILs. Consequently, anti PD-1/PD-L1 checkpoint blocking antibodies provided enhanced efficacy when combined with GUCY2C-CD3. Additionally, significant combination benefit was observed when GUCY2C-CD3 was combined with an anti VEGF-A blocking antibody. Conclusions: Our preclinical data demonstrate that a GUCY2C-CD3 bispecific can selectively target colorectal tumors, including those with KRAS or BRAF mutations, which are difficult to treat with currently approved therapies. This bispecific shows combination benefits with T-cell checkpoint blockade agents, as well as antiangiogenesis agents, indicating that single-agent activity with GUCY2C-CD3 can be further enhanced with mechanisms that address immune evasion. Citation Format: Divya Mathur, Adam Root, Bozena Bugaj-Gaweda, Xingzhi Tan, Wei Fang, Stephanie Bisulco, Jonathan Golas, Jessica Kearney, Eric Upeslacis, Johnny Yao, Edward Rosfjord, Chad Stevens, Lindsay King, Jatin Narula, Kerry Kelleher, Cynthia Rohde, Lioudmila Tchistiakova, Anhco Nguyen, Puja Sapra. A GUCY2c-CD3 bispecific engages T cells to induce cytotoxicity in gastrointestinal tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A16.

Cavity development: a potential biomarker for antiangiogenesis agents.

Thanks for the editors. Thanks for all the suggestions (1,2). The fish models should be modified to further explain the mechanism. The studies about the influence of cavity development on inflammatory, metastatic and autophagy were going on.

Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma-An Overview.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third highest cause of mortality from cancer, largely because of delays in diagnosis. There is currently no effective therapy for advanced stage HCC, although sorafenib, the standard treatment for HCC, systemic therapy (including tyrosine kinase inhibitors and anti-angiogenesis agents), and more recently, immunotherapy, have demonstrated some survival benefit. The measurement and modification of extracellular vesicle (EVs) cargoes—composed of nucleic acids, including miRNAs, proteins, and lipids—holds great promise for future HCC diagnosis, prognosis, and treatment. This review will provide an overview of the most recent findings regarding EVs in HCC, and the possible future use of EVs as “liquid biopsy”-based biomarkers for early diagnosis and as a vehicle for targeted drug-delivery.

Polysaccharide Peptide (PsP) of Ganoderma lucidum as vasa vasorum anti-Angiogenesis agent in Dyslipidemic state by Measuring Lp-PLA2 and H2O2 Levels: In Vivo Study using wistar strain Rattus novergicus model of Atherosclerosis with Dyslipidemia

Polysaccharide Peptide (PsP) of <i>Ganoderma lucidum</i> as vasa vasorum anti-Angiogenesis agent in Dyslipidemic state by Measuring Lp-PLA2 and H₂O₂ Levels<i>: In Vivo</i> Study using wistar strain <i>Rattus novergicus</i> model of Atherosclerosis with Dyslipidemia

Anti-angiogenic activity of uncoated- and N,O-carboxymethyl-chitosan surface modified-Gelucire® 50/13 based solid lipid nanoparticles for oral delivery of curcumin

The co-administration of anti-tumor and anti-angiogenesis agents represents a well-established strategy for cancer treatment. However, the clinical use of this “combined therapy” approach showed several limitations probably due to the inability of most angiogenic inhibitors to target tumor vessels. Herein, we evaluated the in vitro angiogenesis effects of N,O-carboxymethyl chitosan (N,O-CMCS) surface modified curcumin (CUR)-loaded solid lipid nanoparticles (SLN) intended for CUR oral administration. For this purpose, SLN formulations based on Gelucire® 50/13 were prepared and characterized for their physicochemical properties. From stability tests such SLN resulted useful to protect CUR from oxidative and hydrolytic degradation for a long period at 4 °C. Moreover, N,O-CMCS-c-CUR SLN (F4) displayed enhanced cytocompatibility with Caco-2 cells. Data from angiogenesis studies showed that the CUR-unloaded and surface unmodified SLN (b-SLN, F1) possess anti-angiogenic activity and, moreover, due to the features of the coating polysaccharide, F4 may constitute an anti-angiogenic delivery platform for CUR oral delivery and such delivery system seems promising in vascular angiogenesis inhibition.

Abstract A002: Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities

Abstract Angiogenesis plays a critical role in sustaining the microenvironment, growth, and metastatic potential of a variety of tumors, such as lung cancer, colorectal cancer, and renal cancer. However, the rapid development of resistance to anti-angiogenesis agents has limited the clinical benefits. To improve the therapeutic efficacy, the designed dual functional inhibitors, composed of benzophthalazine (anti-angiogenesis moiety) and bis(hydroxymethyl)pyrrole (DNA interstrand crosslinking moiety), were synthesized. We first demonstrated that 1,2-bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazines displayed dual functions, inducing DNA crosslinking and inhibiting angiogenesis. By aid of DIVAA, we confirmed the in vivo anti-angiogenetic activity. They were cytotoxic to a panel of cancer cell lines, including leukemia, colorectal, renal, and lung cancer cells. Among them, small cell lung cancer (SCLC) cells were the most susceptible cells with the IC50 values ranged from subnanomolar to micromolar. Significantly, we observed tumor suppression by treatment of compound 8 in a given formulation at the dose of 20 mg/kg (10 times in 2 weeks) in SCLC H526, squamous lung cancer H520 and renal cancer 786-O xenograft models. In addition, orally admission of 60 mg/kg compound 8 daily for 14 days was also more potent than cisplatin in suppression of growth of SCLC H526 xenografts. Importantly, compound 8 at the dose given did not cause body weight lost. In summary, our results indicate that bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine hybrids are potent than anticancer agents against a wide spectrum of cancers. They deserve our further development. Citation Format: Tai-Lin Chen, Vicky Jain, Anilkumar S. Patel, Yi-Wen Lin, Tsann-Long Su, Te-Chang Lee. Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A002. doi:10.1158/1535-7163.TARG-19-A002

Prognostic value of tumor cavitation in extensive-stage small-cell lung cancer patients treated with anlotinib.

Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. The efficacy of anlotinib as a third-line or beyond therapy for SCLC was confirmed in the ALTER1202 trial. For lung cancer patients treated with antiangiogenesis agents, the phenomenon of cavitation is commonly seen in the lung target lesions. The impact of tumor cavitation on survival in lung cancer patients treated with vascular-targeted therapy remains controversial. Our retrospective study was to investigate the prognostic value of tumor cavitation in extensive-stage SCLC patients treated with anlotinib. A total of 73 extensive-stage SCLC patients confirmed by histopathology from January 2018 to January 2019 were retrospectively analyzed. All patients received anlotinib therapy at Shanghai Chest Hospital. We defined tumor cavitation of the lung target lesions as that part of solid component was changed to air-filled area according to chest CT. Progression-free survival (PFS) was calculated from the beginning of anlotinib therapy to the disease progression or the last follow-up visit. Eleven (15.0%) patients had tumor cavitation during anlotinib therapy. The ORR of the 73 patients was 15.1%. Multivariate logistic regression analysis showed that tumor cavitation during anlotinib therapy was not associated with gender (P = 0.630), age (P = 0.190), smoking status (P = 0.165), anatomy type (P = 0.641), and the line of anlotinib therapy (P = 0.302). The median PFS of all patients was 2.6months (95%CI 2.1-3.2). According to the univariate analysis, the median PFS in patients with and without tumor cavitation was 5.0months and 2.2months, respectively, and the difference was statistically significant (P = 0.041). According to the multivariate analysis, tumor cavitation was an independent factor for PFS after adjusting gender, age, smoking status, anatomy type, the line of anlotinib therapy, tumor cavitation, and response to anlotinib (adjusted HR 0.316, 95%CI 0.142-0.702; P = 0.005). In 73 extensive-stage SCLC patients treated with anlotinib, no demographic/clinical characteristic was related to tumor cavitation, and tumor cavitation was an independent factor in predicting better PFS.

Triptolide inhibits angiogenesis in microvascular endothelial cells through regulation of miR-92a.

Atherosclerosis is one common chronic inflammatory disease in which angiogenesis is involved. Here we established an in vitro cell model of angiogenesis made by human dermal microvascular endothelial cells (HMEC-1) and work to investigate the role of triptolide (TPL) in this model. To induce angiogenesis, HMEC-1 cells were cultured in Matrigel-conditioned medium. The ratio of tubes to nucleus was detected. To evaluate angiogenesis, Western blot assay was carried out to detect endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor receptor-2 (VEGFR2) and VEGF. Cell counting kit-8 was utilized to estimate the viability of HMEC-1 cells. microRNA (miR)-92a was analyzed by qRT-PCR. The targeting relationship between integrin subunit alpha 5 (ITGA5) and miR-92a was verified through luciferase activity assay. The effects of ITGA5 on signaling transducers (ERK, PI3K, and AKT) in a phosphorylated form were valued using Western blot method. After stimulated by TPL, LY294002 and PD98059, the alteration in phosphorylation of the signaling transducers was evaluated by Western blot assay. The ratio of tubes to nucleus and angiogenesis related factors were increased with the delaying of culture time. TPL decreased the expression of angiogenesis factors. Furthermore, miR-92a was upregulated by TPL and miR-92a silence upregulated angiogenesis factors. In addition, TPL decreased ITGA5 which was proved as a target of miR-92a. ITGA5 overexpression resulted in the abundance of angiogenesis factors while ITGA5 silence led to the opposite results. Meanwhile, ITGA5 overexpression increased phosphorylation of ERK, PI3K and AKT while ITGA5 silence reversed the trend. TPL (as an anti-angiogenesis agent) suppressed angiogenesis by upregulating miR-92a, and miR-92a-mediated down-regulation of ITGA5 blocked the signaling transduction of ERK and PI3K/AKT pathways.

Peptide-Conjugated Nanoparticles as Targeted Anti-angiogenesis Therapeutic and Diagnostic in Cancer.

Targeting angiogenesis in the microenvironment of a tumor can enable suppression of tumor angiogenesis and delivery of anticancer drugs into the tumor. Anti-angiogenesis targeted delivery systems utilizing passive targeting such as Enhanced Permeability and Retention (EPR) and specific receptor-mediated targeting (active targeting) should result in tumor-specific targeting. One targeted anti-angiogenesis approach uses peptides conjugated to nanoparticles, which can be loaded with anticancer agents. Anti-angiogenesis agents can suppress tumor angiogenesis and thereby affect tumor growth progression (tumor growth arrest), which may be further reduced with the targetdelivered anticancer agent. This review provides an update of tumor vascular targeting for therapeutic and diagnostic applications, with conventional or long-circulating nanoparticles decorated with peptides that target neovascularization (anti-angiogenesis) in the tumor microenvironment.