Block Angiogenesis Research Articles

A Narrative Review of the Roles of Chondromodulin-I (Cnmd) in Adult Cartilage Tissue.

Articular cartilage is crucial for joint function but its avascularity limits intrinsic repair, leading to conditions like osteoarthritis (OA). Chondromodulin-I (Cnmd) has emerged as a key molecule in cartilage biology, with potential implications for OA therapy. Cnmd is primarily expressed in cartilage and plays an important role in chondrocyte proliferation, cartilage homeostasis, and the blocking of angiogenesis. In vivo and in vitro studies on Cnmd, also suggest an involvement in bone repair and in delaying OA progression. Its downregulation correlates with OA severity, indicating its potential as a therapeutic target. Further research is needed to fully understand the mode of action of Cnmd and its beneficial implications for managing OA. This comprehensive review aims to elucidate the molecular characteristics of Cnmd, from its expression pattern, role in cartilage maintenance, callus formation during bone repair and association with OA.

Green synthesis of nanohydroxyapatite trough Elaeagnus angustifolia L. extract and evaluating its anti-tumor properties in MCF7 breast cancer cell line

BackgroundOne of the most common types of cancer in women is breast cancer. There are numerous natural plant-based products, which exert anti-tumoral effects including Elaeagnus Angustifolia (EA). It modulates cell-cycle process, heat-shock proteins expression, anti-proliferative properties, apoptosis induction, blocking of angiogenesis, and cell invasion inhibition. The current study aimed to synthesize and evaluate the anticancer effects of hydroalcoholic EA extract (HEAE), Nanohydroxyapatite (nHAp) and nHAp synthesized trough EA (nHA-EA) in MCF-7 breast cancer cell line.MethodsIn the present study, HEAE preparation and green synthesis of nHA-EA was done and phase composition, functional groups, and crystallin phase of nHA-EA and nHAp were determined using Fourier-transform infrared (FTIR) and X-ray diffraction (XRD). The characteristics of synthesized nanoparticles including structural and morphological parameters were investigated using scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) techniques. Then, by using MTT-assay (Dimethylthiazoldiphenyltetrazolium), the in vitro cytotoxic and half maximal inhibitory concentration (IC50) of EA extract, nHAp, and nHA-EA in the MCF-7 breast cancer cell line was evaluated. Next, we assessed the expression of apoptosis-related genes Bax, Bcl2 and p53 using quantitative reverse-transcriptase polymerase-chain-reaction (qRT-PCR) and migration of MCF-7 cells by scratch assay.ResultsThe FTIR results demonstrated formation of nHAp and its interaction with HEAE during synthesis process. The XRD results of the synthesized nanoparticles showed similar XRD pattern of nHA-EA and nHAp and purity of synthesized nanomaterials. The average IC50 of HEAE, nHAp, and nHA-EA extract after treatment of cancer cells for 24 h was 400 µg/mL, 200 µg/mL, and 100 µg/mL, respectively. Our results revealed that nHA-EA significantly reduced the migration and invasion of the MCF-7 cells, in comparison to the nHAp and EA extract. Moreover, level of Bax/Bcl2 and p53 was significantly higher in the nHA-EA extract group in comparison to the EA extract and nHAp group.ConclusionTaken together, our results demonstrated that bioactive constituents of EA medicinal plant in form of nHA-EA particles, can effectively exerts potential anticancer and chemo preventive effect against breast cancer growth and can be proposed as a promising beneficial candidate for BC therapy. However, further investigations are required to discover what bioactive compounds are responsible for the chemo preventive effect of this extract.

The Anticancer Effects of Artemisinin and Two Key Derivatives Dihydroartemisinin and Artesunate

Compared to non-malignant cells, cancer cells are better suited to oxidative stress. Reactive oxygen species activity is assumed to be increasing, leading to higher oxidative stress in malignancies. The key derivatives of artemisinin are dihydroartemisinin and artesunate. Oxidative stress, activation of apoptosis, blockage of angiogenesis, and iron sagging are the main findings of artemisinin and its derivatives' anticancer actions. It has been established that the endoperoxide content of artemisinin and its derivatives is of crucial pharmacological significance and is the cause of its anticancer properties. The molecular structure further modification could be a possible way to improve the anticancer capabilities. These properties of artemisinin indicate that it is involved in the oxidative lipid damage that leads to cell death. It shows that the cytotoxicity of artemisinin in vivo is affected by many factors such as vitamin E, holotransferrin and C0-Q10. The vitamins are involved in cell metabolism and very often taken by cancer patients. Further study to investigate the possible impacts in vitro and vivo is necessary.

A phase II study cohort of penpulimab plus anlotinib in patients with recurrent or metastatic non-squamous cell carcinomas of head and neck.

e18013 Background: Recurrent or metastatic non-squamous cell carcinoma of head and neck (R/M non-SCCHN) lack effective systemic treatment. The feasibility of the combination of immune checkpoint inhibitor and anti-angiogenic agents in the treatment of R/M non-SCCHN was unknown. Penpulimab is a novel anti-programmed cell death-1 (PD-1) antibody with complete elimination of FcγR binding activity. Anlotinib is a multi-kinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. ALTN-AK105-II-01 is a single-arm, multi-cohort, multi-center phase II study to investigate the efficacy and safety of penpulimab plus anlotinib in the treatment of various advanced cancers. Here we report the results of the cohort 2 for patients (pts) with R/M non-SCCHN. Methods: Eligible pts were aged 18 years or older and diagnosed with histologically confirmed R/M non-SCCHN. Other inclusion criteria included ECOG PS 0-1 and having at least one measurable lesion according to RECIST 1.1, and anti-angiogenic agents or immune checkpoint inhibitor treatment-naïve. Pts were given penpulimab 200mg intravenously on day 1 and oral anlotinib 12mg once daily from day 1 to day 14 every 3 weeks until disease progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: From May 21, 2020 to October 14, 2020, 21 pts were enrolled in 7 centers in China. The most common site of primary tumor was salivary gland (15/21, 71.4%) and the most common pathological types included adenoid cystic carcinoma (7/21, 33.3%) and duct carcinoma (4/21, 19.0%). 15 pts (71.4%) had distant metastatic lesions and 12 pts (57.1%) had prior chemotherapy history. As of October 20, 2022 (data cut-off), 4 pts achieved confirmed partial response and the ORR was 19.0%. Stable disease (SD) was observed in 17 pts and the DCR was 100%. The median follow-up for PFS was 14.2 months (95%CI: 7.8, 20.6), 9 pts suffered disease progression and the median PFS was 10.6 months (95%CI: 0.0, 22.4). 14 pts (66.7%) experienced at least one ≥grade 3 treatment-related adverse events (TRAEs) and the most common ≥grade 3 TRAEs was hypertension (15.0%). No treatment-related death was reported. Conclusions: The combination of penpulimab and anlotinib showed encouraging efficacy and favorable safety profile in R/M non-SCCHN and is worthy of further investigation. Clinical trial information: NCT04203719 .

Hsa-miR-22-3p inhibits liver cancer cell EMT and cell migration/ invasion by indirectly regulating SPRY2.

The general mechanism for microRNAs to play biological function is through their inhibition on the expression of their target genes. In cancer, microRNAs may accelerate cell senescence, block angiogenesis, decrease energy supplies, repress tumor cell cycle and promote apoptosis to function as the tumor repressors. On the other hand, microRNAs can modulate tumor suppressor molecules to activate oncogene relevant signaling pathway to initiate tumorigenesis and promote tumor progression. By targeting different genes, miR-22 can function as either a tumor suppressor or a tumor promoter in different types of cancer. In liver cancer, miR-22 mainly functions as a tumor suppressor via its regulation on different genes. In this study, we demonstrated that miR-22 indirectly regulates SPRY2 by inhibiting CBL, an E3 ligase for SPRY2 that has been confirmed. As one of the modulators of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathway, SPRY2 plays important roles in many developmental and physiological processes, and its deregulation has been reported in different types of cancer and shown to affect cancer development, progression, and metastasis. By inhibiting the expression of CBL, which stabilizes SPRY2, miR-22 indirectly upregulates SPRY2, thereby suppressing the epithelial-mesenchymal transition (EMT), cell migration, and invasion and decreasing the expression of liver cancer stem cell (CSC) marker genes. The inhibitory effects of miR-22 on EMT, cell migration, and invasion can be blocked by the knockdown of SPRY2 expression in miR-22 overexpressing cells. Additionally, we demonstrated that miR-22 expression inhibits the ERK signaling pathway and that this effect is due to its upregulation of SPRY2. Overall, our study revealed a novel miR-22-3p/CBL/SPRY2/ERK axis that plays an important role in EMT, cell migration, and invasion of liver cancer cells.

Honokiol inhibits interleukin-induced angiogenesis in the NSCLC microenvironment through the NF-κB signaling pathway

Tumor angiogenesis, which may be affected by microenvironmental inflammation and promotes tumor development and metastasis, is one of the key reasons contributing to increased mortality. The goal of this study is to investigate how lignin analogs, specifically honokiol (HNK), block angiogenesis induced by the inflammatory milieu of lung cancer. The human lung cancer cell lines A549 and H460 were treated with HNK. Interleukin-1 was employed to mimic an inflammatory tumor microenvironment. Findings demonstrated that HNK drastically decreased the cell viability of A549 and H460 cells. In A549 and H460 cells, HNK also reduced the production of vascular endothelial growth factor (VEGF), the most important marker of tumor angiogenesis. Signal pathway studies revealed that HNK blocked the NF-κB signaling pathway. This effect, in turn, prevented the expression of VEGF by inhibiting the NF-κB signaling pathway. Human umbilical vein endothelial cells (HUVECs) from A549-conditioned medium cultures were subjected to HNK treatment, which decreased tubulogenesis, horizontal and vertical migration, and cell proliferation in HUVECs. Overall, HNK inhibited the NF–κB pathway. This effect resulted in the downregulation of VEGF, thus reducing the viability and angiogenesis of human lung cancer cell lines. In A549 cell xenografts, HNK decreased VEGF expression, tumor angiogenesis, and tumor development. Our research shows that HNK is a potential antiangiogenic molecule for the treatment of lung cancer.

Structure, selenization modification, and antitumor activity of a glucomannan from Platycodon grandiflorum

Platycodon grandiflorum is consumed popularly as a nutritional and healthy plant in East Asia, which has multiple medicinal functions. As an exploration to elucidate the beneficial ingredients, an acetylated glucomannan (PGP40-1) was purified from P. grandiflorum. Structural analysis showed that PGP40-1 was composed of →4)-β-Manp-(1→, →4)-β-Glcp-(1→, →6)-β-Glcp-(1→, and terminal α-Glcp-(1→. PGP40-1 was found to possess weak antitumor activity in vitro, which was thus modified to afford a selenized polysaccharide (Se-PGP40-1) by the HNO3/Na2SeO3 method. Se-PGP40-1 showed significant antitumor activity in cell and zebrafish models, which could inhibit tumor proliferation and migration by inducing cell apoptosis and blocking angiogenesis. The research not only clarifies the ingredients of P. grandiflorum with high economical value, but also affords a potential antitumor agent originating from the plant polysaccharide.

EP16.04-031 Connexin 43 Overexpression Induces Angiogenesis in Vitro Following Phosphorylation at Ser279 in its C Terminus

Blocking angiogenesis can inhibit tumor growth and metastasis. However, the mechanism underlying regulation of lung cancer angiogenesis remains unclear. The gap junction protein connexin 43 (Cx43) is implicated in angiogenesis. We aimed to determine the role of Cx43 in angiogenesis in vitro and its signal pathways.

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma

BackgroundLenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC).MethodsThis study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3−) to nitrite (NO2−) with nitrate reductase, followed by quantitation of NO2− based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE.ResultsAfter lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (p = 0.029 and p = 0.005, respectively).ConclusionDecreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

Connexin 43 overexpression induces lung cancer angiogenesis in vitro following phosphorylation at Ser279 in its C-terminus.

Blocking angiogenesis can inhibit tumor growth and metastasis. However, the mechanism underlying regulation of lung cancer angiogenesis remains unclear. The gap junction protein connexin 43 (Cx43) is implicated in angiogenesis. The aim of the present study was to determine the role of Cx43 in angiogenesis in vitro and its signaling pathways. Human pulmonary microvascular endothelial cells were transfected with Cx43-targeting siRNA or Cx43-overexpressing recombinant plasmid vector. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to determine Cx43, zonula occludens-1 (ZO-1), E-cadherin, β-catenin, von Willebrand factor (vWF), and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein expression levels, respectively. Tyr265, Ser279, Ser368, and Ser373 phosphorylation levels in the C-terminus of Cx43 and intracellular and membranal Cx43 contents were determined using western blotting. Additionally, immunofluorescence, tube formation, Cell Counting Kit-8, and Transwell migration assays were performed. The results revealed that compared with that in the control samples, Cx43, ZO-1, E-cadherin, β-catenin, vWF, and PAI-1 mRNA and protein expression were significantly increased in the Cx43 overexpression group and significantly decreased in the Cx43-knockdown group. Moreover, the phosphorylation level of Ser279 as well as cell proliferation and migration rates were markedly increased in the Cx43 overexpression group, and tube formation revealed that the potential of angiogenesis was also increased. Conversely, in the Cx43-knockdown group, the phosphorylation level of Ser279 and cell proliferation and migration rates were reduced, and the potential of angiogenesis was greatly impaired. Under Cx43 overexpression, membranal Cx43 content was significantly increased, whereas under Cx43 knockdown, it was significantly reduced. Therefore, Cx43 overexpression could induce pulmonary angiogenesis in vitro by promoting cell proliferation and migration and activating ZO-1, E-cadherin, β-catenin, vWF, and PAI-1. This may be achieved by promoting phosphorylation and activation of the intracellular signal site Ser279 at the C-terminus of Cx43.

Ligustilide Inhibits Tumor Angiogenesis by Downregulating VEGFA Secretion from Cancer-Associated Fibroblasts in Prostate Cancer via TLR4.

Simple SummaryInhibiting the production of vascular endothelial growth factor A (VEGFA) can inhibit angiogenesis, thereby inhibiting tumor growth. We found that ligustilide can inhibit the secretion of VEGFA from prostate cancer-related fibroblasts (CAFs), and this signaling pathway is related to Toll-like receptor 4 (TLR4)-ERK/JNK/p38. Using the above receptors or signals pathway molecule blockers can block the effect of ligustilide to downregulate the secretion of VEGFA from CAFs. The concentration of ligustilide used in this study does not directly inhibit the growth of CAFs, but changes its function, and this study is different from the direct blocking effect of the existing VEGFA antibodies, but cuts off the source of VEGFA, which is expected to become a novel therapeutic strategy for oncology.CAFs secrete VEGFA in the tumor microenvironment to induce angiogenesis and promote tumor growth. The downregulation of VEGFA secretion from CAFs helps block angiogenesis and exerts an anti-tumor effect. In vivo experiments showed that the angiogenesis of the tumor-bearing mice in the ligustilide group was significantly reduced. The results of MTT, tube formation, Transwell and scratch experiments showed that ligustilide did not affect the proliferation of HUVECs in a certain concentration range (<60 μM), but it inhibited the proliferation, tube formation and migration of HUVECs induced by CAFs. At this concentration, ligustilide did not inhibit CAF proliferation. The qPCR and WB results revealed that ligustilide downregulated the level of VEGFA in CAFs via the TLR4-ERK/JNK/p38 signaling pathway, and the effect was attenuated by blockers of the above molecules. Ligustilide also downregulated the autocrine VEGFA of HUVECs induced by CAFs, which inhibited angiogenesis more effectively. In addition, ligustilide inhibited glycolysis and HIF-1 expression in CAFs. Overall, ligustilide downregulated the VEGFA level in CAFs via the TLR4-ERK/JNK/p38 signaling pathway and inhibited the promotion of angiogenesis. This study provides a new strategy for the anti-tumor effect of natural active molecules, namely, blockade of angiogenesis, and provides a new candidate molecule for blocking angiogenesis in the tumor microenvironment.

Preparation and structural properties of selenium modified heteropolysaccharide from the fruits of Akebia quinata and in vitro and in vivo antitumor activity

Cancer is a complex disease, and blocking tumor angiogenesis has become one of the most promising approaches in cancer therapy. Here, an exopoly heteropolysaccharide (AQP70-2B) was firstly isolated from Akebia quinata. Monosaccharide composition indicated that the AQP70-2B was composed of rhamnose, glucose, galactose, and arabinose. The backbone of AQP70-2B consisted of →1)-l-Araf, →3)-l-Araf-(1→, →5)-l-Araf-(1→, →3,5)-l-Araf-(1→, →2,5)-l-Araf-(1→, →4)-d-Glcp-(1→, →6)-d-Galp-(1→, and →1)-d-Rhap residues. Based on the close relationship between selenium and anti-tumor activity, AQP70-2B was modified with selenium to obtain selenized polysaccharide Se-AQP70-2B. Then, a series of methods for analysis and characterization, especially scanning electron microscopy coupled with energy dispersive spectrometry (SEM-EDS), indicated that Se-AQP70-2B was successfully synthesized. Furthermore, zebrafish xenografts and anti-angiogenesis experiments indicated that selenization could improve the antitumor activity by inhibiting tumor cell proliferation and migration and blocking angiogenesis.

908P Efficacy and safety of penpulimab plus anlotinib in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): A phase II study

Penpulimab is a newly developed programmed cell death-1 monoclonal antibody with complete elimination of FcγR binding and ADCC/ADCP. A phase II study (ALTN-AK105-II-01, NCT04203719) was designed to explore the efficacy and safety of penpulimab plus anlotinib, a multikinase inhibitor blocking angiogenesis and proliferation, in the treatment of patients (pts) with several advanced cancers. Here we report the preliminary results for the cohort of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Abstract 1063: Effectiveness of Tumor Treating Fields (TTFields) in combination with sorafenib for treatment of hepatocellular carcinoma in vitro and in vivo

Abstract Purpose/Objective(s): Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and it is one of the leading causes of related mortality worldwide. Sorafenib is an oral multikinase inhibitor that targets the Raf/MEK/ERK signaling pathway, thus inducing autophagy and blocking angiogenesis. Sorafenib is approved for advanced HCC and is the main first-line chemotherapy, yet its survival benefits are limited. Tumor Treating Fields (TTFields) therapy is an anticancer treatment that is non-invasively and locoregionally delivered to tumor bed via low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. Since HCC is a complex, heterogeneous tumor with exhibited aberrant signaling pathways, sorafenib combined with additional chemotherapy agents and other types of treatment modalities, such as TTFields, may be a feasible option for targeting HCC. The purpose of this study was to explore the use of TTFields, alone and in combination with sorafenib, for HCC treatment. Materials/Methods: HCC cell lines (HepG2 and Huh-7D12) were treated for 72 hours with TTFields at various frequencies. Efficacy of TTFields and sorafenib combination was tested by applying optimal frequency TTFields in the presence of various concentrations of sorafenib. Cytotoxicity, apoptosis, and clonogenicity were determined, and overall effect was calculated as the product of the cytotoxic and clonogenic effects. Changes in autophagy levels were also examined. In vivo, N1S1 HCC cells (50,000) were orthotopically injected into the left hepatic lobe of SD rats. After 1 week, TTFields at the optimal frequency were continuously applied for 6 days to the abdominal region of rat torsos, and sorafenib (10 mg/kg/day) was injected daily. Tumor volume growth was determined by MRI. Results: The TTFields frequency assessed for optimally treating HCC cell lines was 150 kHz. Cells were sensitive to sorafenib in a dose-dependent manner, and concomitant addition of TTFields augmented this effect. The effect of TTFields, like that of sorafenib, was demonstrated to be related to increases in autophagic flux. In the animal model, tumor growth was significantly reduced in the combination group compared to other treatment groups. Conclusion: These results demonstrate that TTFields are effective for the treatment of HCC and may further enhance effectiveness in combination with standard of care chemotherapy. The ongoing phase 2 HEPANOVA (NCT03606590) clinical trial will investigate the safety and efficacy of TTFields plus sorafenib combination in patients with unresectable, locally advanced HCC. Citation Format: Shiri Davidi, Anna Shteingauz, Sara Jacobovitch, Karnit Gotlib, Catherine Tempel-Brami, Mijal Munster, Einav Zeevi, Eyal Dor-On, Rosa S. Schneiderman, Tali Voloshin, Adi Haber, Moshe Giladi, Adrian Kinzel, Uri Weinberg, Yoram Palti. Effectiveness of Tumor Treating Fields (TTFields) in combination with sorafenib for treatment of hepatocellular carcinoma in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1063.

Anlotinib alone or in combination with temozolomide in recurrent high-grade glioma: A retrospective study.

e14019 Background: High-grade glioma (HGG) is the most common malignant brain tumor and lacks effective treatment regimen. Anlotinib is a multikinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. This study was performed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide (TMZ) in the treatment of recurrent HGG. Methods: This is a single-center, retrospective study. Eligible patients (pts) were diagnosed with pathologically confirmed high grades (WHO III/IV) glioma and had recurrent or progressive disease on or after prior treatment. Other key eligibility criteria included Karnofsky Performance Status (KPS) ≥ 40, aged 16 ̃75 years and having at least one measurable lesion (RANO criteria). Pts were administrated with anlotinib once daily for 14 days every 3 weeks till disease progression, intolerable toxicities or death. The initial dose was 12mg for younger pts ( &lt; 40 years old) with KPS ≥ 60 and 10 mg for others. Combination treatment was allowed if previous TMZ was effective and tolerable. TMZ was administered on dose-dense schedule (150mg/m2, QD, d1-d7 and d15-d21 every 28 days) or metronomic schedule (25-50mg/m2 QD). The primary endpoint was progression-free survival at 6 months (PFS6m) accessed according to RANO criteria. The second endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Between August 2019 and June 2020, 23 pts with HGG (15 grade IV; 8 grade III; 12 males, 11 females) were enrolled. The median age and median KPS was 42 years and 60. 16 pts have multifocal or disseminated disease. 18 pts received ≥2 lines previous treatment. At the data cutoff date on September 2020, the median duration of treatment was 9 weeks (range: 3-33). The PFS6m was 39.1% and the median PFS was 4.2 months (95% CI: 2.8, 5.6). The median OS was not reached (95% CI: NE, NE) and the OS at 12 months (OS12m) was 54.8%. 8 pts observed tumor response and 9 pts had stable disease. The ORR and DCR were 34.8% and 73.9% respectively. The results of survival analysis for subgroups were summarized in table below. Grade 1 or 2 treatment-related adverse events (TRAEs) occurred in 65.2% pts. No ≥ grade 3 TRAE was found. All hematological TRAEs occurred in patients received combination regimen. No TRAE-induced treatment termination occurred. The lower incidence of TRAE may partly attributed to that most pts (18/23) received lower initial dose (10mg) of anlotinib and the relatively shorter treatment duration. Conclusions: This study showed treatment with anlotinib alone or in combination with TMZ had promising efficacy and favorable tolerability in patients with recurrent HGG.[Table: see text]

Endothelial cell plasticity at the single-cell level

The vascular endothelium is characterized by a remarkable level of plasticity, which is the driving force not only of physiological repair/remodeling of adult tissues but also of pathological angiogenesis. The resulting heterogeneity of endothelial cells (ECs) makes targeting the endothelium challenging, no less because many EC phenotypes are yet to be identified and functionally inventorized. Efforts to map the vasculature at the single-cell level have been instrumental to capture the diversity of EC types and states at a remarkable depth in both normal and pathological states. Here, we discuss new EC subtypes and functions emerging from recent single-cell studies in health and disease. Interestingly, such studies revealed distinct metabolic gene signatures in different EC phenotypes, which deserve further consideration for therapy. We highlight how this metabolic targeting strategy could potentially be used to promote (for tissue repair) or block (in tumor) angiogenesis in a tissue or even vascular bed-specific manner.

Structural analysis and biological effects of a neutral polysaccharide from the fruits of Rosa laevigata

A neutral water-soluble polysaccharide (RLP50-2) was extracted and purified from the fruits of Rosa laevigata. The absolute molecular weight was determined as 1.26 × 104 g/mol. Monosaccharide composition analysis showed that RLP50-2 mainly consisted of glucose, arabinose, and galactose. Structural analysis revealed that RLP50-2 consisted of →5)-α-L-Araf-(1→, →2,5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, →4)-α-D-Glcp-(1→, →6)-α-D-Glcp-(1→, →3,6)-β-D-Glcp-(1→, →4)-α-D-Galp-(1→, →6)-β-D-Galp-(1→, →2)-β-D-Xylp-(1→, terminal α-L-arabinose, and terminal β-D-mannose. Biological assays showed that RLP50-2 had immunomodulatory activities using cell and zebrafish models. Moreover, RLP50-2 showed significantly antitumor activities by inhibiting tumor cell proliferation and migration and blocking angiogenesis. These results suggested that RLP50-2 could be developed as a potential immunomodulatory agent or antitumor candidate drug in biomedicine field.

Research update on the anticancer effects of buparlisib.

Buparlisib is a highly efficient and selective PI3K inhibitor and a member of the 2,6-dimorpholinopyrimidine-derived family of compounds. It selectively inhibits four isomers of PI3K, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, by competitively binding the lipid kinase domain on adenosine 5'-triphosphate (ATP), and serves an important role in inhibiting proliferation, promoting apoptosis and blocking angiogenesis, predominantly by antagonizing the PI3K/AKT pathway. Buparlisib has been confirmed to have a clinical effect in patients with solid tumors and hematological malignancies. A global, phase II clinical trial with buparlisib and paclitaxel in head and neck squamous cell carcinoma has now been completed, with a manageable safety profile. Buparlisib currently has fast-track status with the United States Food and Drug Administration. The present review examined the biochemical structure, pharmacokinetic characteristics, preclinical data and ongoing clinical studies of buparlisib. The various mechanisms of influence of buparlisib in tumors, particularly in preclinical research, were summarized, providing a theoretical basis and direction for basic research on and clinical treatment with buparlisib.

Anlotinib has good efficacy and low toxicity: a phase II study of anlotinib in pre-treated HER-2 negative metastatic breast cancer.

Objective:Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer.Methods:Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5–10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers.Results:Twenty-six eligible patients were enrolled, with a median age of 56 (30–75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86–6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroid-stimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%).Conclusion:Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.

Assessment of quality and clinical similarity (pharmacokinetic and safety) of HD204, a biosimilar of bevacizumab.

e21556 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar candidate of Bevacizumab (Avastin). Bevacizumab has been approved in the treatment of a variety of metastatic tumours. Bevacizumab, a recombinant humanized monoclonal antibody block angiogenesis which is required for cancer progression by preventing binding of soluble vascular endothelial growth factor (VEGF) to VEGF receptors. Due to heterogeneity nature of antibody therapeutic, the impact on quality of HD204 on safety and pharmacokinetic (PK) was reaffirmed through clinical study to establish clinical similarity between HD204 and Avastin. Methods: Quality attributes identified to influence PK and safety established through comprehensive analytical characterization was used to correlate any potential differences (structural or biological) between the two compounds if any, could result in any clinical meaningful differences in safety and PK in the clinical settings. The PK and safety equivalence of HD204 relative to Avastin was demonstrated in a randomized, single-blind, single-dose, three-arm and parallel-group study clinical Phase I (SAMSON). A total of 120 healthy male subjects randomized 1:1:1 were to receive 1 mg/kg intravenous infusion of either HD204, EU- or US-Avastin. Various PK parameters, safety assessments not limiting to adverse events (AE) and measurement of antidrug antibodies (ADA) and neutralizing antibodies (NAb) were evaluated. Results: The pairwise comparisons of Exposure (AUC0-inf and AUC0-last), maximal concentration (Cmax) established equivalence between the 3 arms. All other PK parameters including half-life, clearance and volume of distribution were comparable between HD204 and Avastin treatment groups. Treatment related TEAEs reported for each group were 25.0%, 30.0% and 25.6% respectively and comparable. There were no treatment-emergent SAEs. Furthermore, none of the subjects treated with HD204 was ADA positive. Conclusions: HD204 demonstrated equivalent PK and safety profile to both US-Avastin and EU-Avastin at 1mg/kg administered as a 90-minute IV infusion to healthy male subjects. A prospective clinical study aimed to demonstrate equivalence in terms of efficacy, PK and safety is currently ongoing. Clinical trial information: 2017-005174-19.