First line anlotinib plus liposomal doxorubicin for locally advanced or metastatic soft tissue sarcoma: A prospective, single-arm trial

Objective: To examine the efficacy and safety of anlotinib as firstline therapy to treat locally advanced or metastatic soft-tissue sarcoma. Methods: This is a single-arm trial. Treatment-naive patients (≥14 years) with locally advanced or metastatic soft tissue sarcoma were eligible. Each treatment cycle lasted for 3 weeks, and included liposomal doxorubicin (40-50 mg/m2) on day 1 and anlotinib (12 mg) on days 8-21. Starting from the 9th cycle, treatment consisted of only anlotinib. Treatment continued until disease progression or intolerable toxicities. The primary efficacy end point was progression-free survival (PFS). Results: Eight patients were enrolled between July 25, 2019 and January 8, 2020. The median number of treatment cycles was 5.5. Within 5.9 months median follow-up, PFS events occurred in 4 (4/8, 50%) patients. The median PFS was 11.3 months and the 6-month PFS rate was 56%. No patients attained complete response and 2 patients (fibrosarcoma, 1 patient and undifferentiated pleomorphic sarcoma, 1 patient) achieved partial response. Three patients (fibrosarcoma, 2 patients and synovial sarcoma, 1 patient) had stable disease. The objective response rate was 25% (2/8) for the study population, and the disease control rate was 75% (6/8). No new safety concerns emerged. Conclusions: Anlotinib plus liposomal doxorubicin demonstrated antitumor activities in previously untreated locally advanced or metastatic soft tissue sarcomas. Due to the small sample size, further investigations with a larger population should be undertaken to confirm the study findings.

Prospective study of apatinib combined with chemoradiotherapy for head and neck squamous cell carcinoma / 中华放射肿瘤学杂志

Objective:To evaluate the efficacy and safety of apatinib in combination with chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC).Methods:37 patients orally received apatinib at 250 mg/d during concurrent chemoradiotherapy until completion of radiotherapy, complete remission assessed by imaging examination, the onset of unacceptable toxicity or death. Baseline characteristics, objective response rates (ORR) and adverse events were assessed in all enrolled patients with complete baseline and safety data. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method. Prognostic factors were statistically identified using Cox regression models.Results:The ORR was 85%(95% CI: 72%-98%). The median PFS was 17.9 months and the 2-year OS rate was 62%(95% CI: 48%-80%). Ineffective short-term efficacy ( HR=0.035, 995% CI: 0.02-0.652, P=0.025) was an independent risk factor for poor OS. In addition, ineffective short-term efficacy ( HR=0.104, 95% CI: 0.017-0.633, P=0.014) and lymphocytopenia ( HR=17.539, 95% CI: 2.040-150.779, P=0.009) were independent risk factors for poor PFS. Common adverse events (>60%) included lymphocytopenia (76%), leukopenia (68%) and irradiation-induced mucosal injury (65%). The most common treatment-associated grade 3 adverse event was lymphopenia (49%). Conclusions:Apatinib combined with chemoradiotherapy yield significant anti-tumor activity for HNSCC with controllable toxicity. For patients with advanced HNSCC, short-term efficacy and lymphocytopenia may be potential predictors for clinical efficacy of apatinib combined with chemoradiotherapy.

Anti-angiogenesis in Lung Cancer: Current Situation, Progress and Confusion / 中国肺癌杂志

Lung cancer is a highly vascular tumors, over the past ten years, anti-angiogenes is has been proved to be an effective and highly promising combinational treatment. The data of the combination of anti-angiogenesis with chemotherapy, targeted therapy, immunotherapy has been constantly updating. Advanced lung cancer patients, no matter different groups or different stages of the disease, are benefited from anti-angiogenes. In this paper, based on the clinical status and unsolved problems, combined with the latest clinical and translational research data, we reviewed the current anti-angiogenesis treatment of lung cancer.
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Advances in Treatment of Brain Metastasis from Lung Cancer / 肿瘤防治研究

Lung cancer is the malignant tumor with the highest incidence and mortality in China, and is prone to brain metastasis in the process of disease development, which seriously affects the quality of life and survival of patients. The treatment methods for brain metastasis of lung cancer include surgery, chemotherapy, whole brain radiotherapy, stereotactic radiosurgery, molecular targeted therapy, immunotherapy, anti-angiogenesis therapy, etc. It's one of the research hotspots to choose reasonable and effective treatment schemes for different patients. This paper reviews the research progress in the treatment of brain metastasis from lung cancer, to provide reference for selecting more reasonable clinical treatment for the patients.

Advances in research on therapeutic strategies of targeting pancreatic cancer stroma / 中国药科大学学报

@#Pancreatic cancer stroma plays a critical role in tumor progression, invasion, metastasis and resistance.Targeting tumor cell alone could not meet the demand for prolonging patients'' survival.Growing studies have laid emphasis on developing combined regimens between targeting pancreatic cancer stroma and chemotherapy, radiotherapy and immunotherapy.We are faced with some new opportunities in spite of the great challenges brought to the research and development of targeting drugs owing to the complicated stroma components, crosstalking signal pathways and abnormal angiogenesis of pancreatic cancer.In this article, recent advances in therapeutic strategies of targeting pancreatic cancer stroma are reviewed and analyzed from the aspects of extracellular matrix (ECM), cancer associated fibroblasts (CAFs) and vessels, in the hope of providing some novel ideas for targeting therapy against pancreatic cancer.

Response of Lung Adenocarcinoma Harbouring Sensitizing EGFR Mutation to the Fourth-line Combination Treatment of Pembrolizumab and Anlotinib / 中国肺癌杂志

45.7% of Chinese patients with advanced lung adenocarcinoma were reported to harbour sensitizing epidermal growth factor receptor (EGFR) mutations. Limited therapeutic options are left for non-small cell lung cancer (NSCLC) harbouring sensitizing EGFR mutations after failure of EGFR-tyrosine kinase inhibitor (TKI) therapy and chemotherapy, finding effective options for them is an unmet clinic need. Herein we reported a case that till January 12, 2021, an 82-year-old female with sensitizing EGFR-mutant advanced lung adenocarcinoma received a surprising progression-free survival (PFS) benefit of over 21 months from the combination therapy of pembrolizumab and anlotinib after her failure of treatments of osimertinib, chemotherapy and anlotinib-monotherapy.
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Injectable thermo-responsive nano-hydrogel loading triptolide for the anti-breast cancer enhancement

The clinical application of triptolide (TPL) in tumor therapy has been greatly limited by its toxicity and inefficient delivery. Herein, a localized and sustained-release thermo-sensitive hydrogel was developed for the intra-tumor administration of TPL. Based on the amphiphilic structure of poly (

Manipulation of immune‒vascular crosstalk: new strategies towards cancer treatment

Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors, endogenous immune surveillance and immune cell function. Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels, thus improving immune stimulation and the efficacy of immunotherapy. Interestingly, the presence of "immune‒vascular crosstalk" enables the formation of a positive feedback loop between vascular normalization and immune reprogramming, providing the possibility to develop new cancer therapeutic strategies. The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties. Here, we reviewed the recent advances of effective routes, especially nanomedicine, for normalizing tumor vasculature. We also summarized the development of enhancing nanoparticle-based anticancer drug delivery

Consensus on the safety management of anti-angiogenic tyrosine kinase inhibitors in bone and soft tissue sarcoma treatment / 中国肿瘤临床

Anti-angiogenesis-targeted drugs, especially anti-angiogenic tyrosine kinase inhibitors (aa-TKIs), are broadly used in the treatment of advanced bone and soft tissue sarcoma. The antitumor effects of Chinese domestically developed aa-TKIs, such as apatinib and anlotinib, were also demonstrated in several single-center or multi-center clinical studies. However, treatment-related adverse events (AEs) have limited the use of aa-TKIs. On Aug 30, 2019, the members of the Chinese Sarcoma Study Group conducted a thorough discussion on this issue and reached a consensus, focusing on the classification and treatment of common AEs that may occur during the use of aa-TKIs. The aim of this article is to improve our understanding and provide AE management guidance for clinicians as well as benefit patients using aa-TKIs.

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR simultaneously . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check / 医学前沿

In terms of global cancer-related deaths, hepatocellular carcinoma (HCC) has the fourth highest mortality rate. Up until 2017, treatment of advanced HCC was largely limited to sorafenib, an oral tyrosine kinase inhibitor, with little to no success in the development of alternative treatment options. However, in the past two years, there has been an unprecedented increase in both the number and type of treatment options available for HCC. As of 2019, the US FDA has approved four oral tyrosine kinase inhibitors, two immune checkpoint inhibitors, and one anti-angiogenesis antibody for the treatment of HCC. Even with this new variety, systemic treatment of advanced HCC remains largely unsatisfactory, and the median survival rate stands at approximately one year. The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019. The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or anti-angiogenesis medications is the current clinical research trend, the results of which are eagerly anticipated. Despite limited progress in survival, HCC research is currently experiencing a period of growth and innovation, and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.

Green synthesis of zinc oxide nanoparticles and evaluation of anti-angiogenesis, anti-inflammatory and cytotoxicity properties

In this study, zinc oxide nanoparticles (ZnO-NPs) were synthesized using the extract of Hyssops officinalis L. via greenmethod and confirmed by transmission electron microscopy, field emission scanning electron microscopy, X-ray powderdiffraction and Fourier transforms infrared spectroscopy techniques. In the in vivo section, the anti-angiogenesis and antiinflammatory properties of the NPs were evaluated by the chorioallantoic membrane (CAM) assay and mouse paw edematest (induced by carrageenan), respectively. In the in vitro section, changes in the expression of angiogenesis genes (VEGFand VEGFR) and inflammatory genes (IL-1B and IL-10) were investigated by real-time quantitative polymerase chainreaction technique. In order to evaluate the cytotoxicity of ZnO-NPs, 3-5, 4-dimethylthiazol-2-yl) -5, 2-tetrazolium bromide(MTT) test was used on MDA-MB231 breast adenocarcinoma cell line. The results of the CAM assay showed that theZnO-NPs significantly reduced the number and length of blood vessels, as well as the size and weight of the embryos.Evaluation of mouse paw edema showed that the NPs are able to decrease inflammation. Changes in the expression patternof VEGF and VEGFR genes in MCF7 cells showed that the NPs have inhibitory effect on the expression of both genes.Expression levels of IL-10 and IL-1B genes also increased and decreased, respectively. The MTT test showed that the NPhave the ability to decrease breast cancer cells. In conclusion, our results confirm that the ZnO-NPs synthesized by greenmethod have promising anti-cancer properties.

Synthesis and anti-angiogenic activity of a novel microtubule inhibitor IMB5046 / 药学学报

IMB5046 is a newly discovered nitrobenzoate functioning as a microtubule inhibitor. Here we report its synthesis and in vitro anti-angiogenic activity. IMB5046 was synthesized by conjugation of 2-morpholin-4-yl-5-nitrobenzoic acid with 4-(methylthio)benzyl alcohol via two-step reactions. The structure of the end product was verified using 1H NMR and HR-MS spectroscopy. The effect of these compounds on cell proliferation was determined using MTT assay, and their impact on cytoskeleton was investigated using fluorescence assay. Flow cytometry was performed to examine the effect of IMB5046 on cell cycle. Cell wound scratch assay and Transwell assay were performed to examine cell migration. Endothelial tube formation assay was used to evaluate the anti-angiogenic activity of IMB5046. The results indicated that IMB5046 induced endothelial cell contraction and microtubule depolymerization, and inhibited the proliferation of endothelial cells and tumor cells, while two raw materials showed no obvious effects. IMB5046 arrested cell cycle at G2/M phase, even at low-cytotoxic concentrations it significantly inhibited the motility of endothelial cells. IMB5046 inhibited the tube formation of endothelial cells according to the number of tubes and junctions. In conclusion, IMB5046 is a promising microtubule-targeting drug with anti-angiogenic activity.

Isolation of dihydrobenzofuran derivatives from ethnomedicinal species Polygonum barbatum as anticancer compounds

BACKGROUND: Ethnomedicinally, the family Polygonaceae is famous for the management of cancer. Various species of this family have been reported with anticancer potentials. This study was designed to isolate anticancer compounds from ethnomedicinally important species Polygonum barbatum. METHODS: The column chromatography was used for the isolation of compounds from the solvent fraction of P. barbatum. The characterization of isolated compounds was performed by various spectroscopic techniques like UV, IR, mass spectrometry and 1D-2D NMR spectroscopy. Keeping in view the ethnomedicinal importance of the family, genus and species of P barbatum, the isolated compounds (1-3) were screened for anticancer potentials against oral cancer (CAL-27) and lungs cancer (NCI H460) cell lines using MTT assay. Active compound was further investigated for apoptosis by using morphological changes and flow cytometry analysis. In vivo anti-angiogenic study of the isolated compounds was also carried using chorioallantoic membrane assay. Docking studies were carried out to explore the mechanism of anticancer activity. RESULTS: Three dihydrobenzofuran derivatives (1-3) have been isolated from the ethyl acetate fraction of P. barbatum. The structures of isolated compounds were elucidated as methyl (2S,3S)-2-(3,4-dimethoxyphenyl)-4-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-7-methoxy-2,3-dihydrobenzo-furan-3-carboxylate (1), (E)-3-((2S,3S)-2-(3,4-dimethoxyphenyl)-7-methoxy-3-(methoxy carbonyl)-2,3-dihydrobenzofuran-4-yl)acrylic acid (2) and (2S,3 S)-4-((E)-2-carboxyvinyl)-2-(3,4-dimethoxyphenyl)-7-hydroxy-2,3-dihydrobenzofuran-3-carboxylic acid (3). The compound 1 was found to be more potent with IC50 of 48.52 ± 0.95 and 53.24 ± 1.49 against oral cancer cells as compared to standard drug (IC50 = 97.76 ± 3.44 µM). Both compound also inhibited lung cancer cells but at higher concentrations. Morphological and flow cytometry analysis further confirms that compound 1 induces apoptosis after 24 to 48 h treatment. In antiangiogenesis assay, compounds 1, 2 and 3 exhibited IC50 values of 8.2 ± 1.1,13.4 ± 1.1 and 57.7 ± 0.3 µM respectively. The docking studies revealed that the compounds under study have the potential to target the DNA and thymidylate synthase (TS). CONCLUSION: Based on its overwhelming potency against the tested cell lines and in angiogenesis assay, compound 1 can be further evaluated mechanistically and can be developed as anticancer drug candidate.

Experimental study of anti-metastasis effects of HUVEC vaccine combined with chemotherapy in EMT-6 breast cancer / 中国免疫学杂志

Objective:To investigate whether human umbilical vein endothelial cell(HUVEC) vaccine combined with low dose docetaxel (DOC) could play a synergistic role in anti-breast cancer.Methods:BALB/c mice were randomly divided into normal saline group,HUVEC vaccine group,DOC group,and HUVEC vaccine combined with DOC treatment group (HUVEC-DOC) group.An experimental metastasis model by tail vein injection of EMT-6 breast cancer cells was employed to evaluate the anti-metastatic efficiency of the HUVEC-DOC combination treatment regime.Lymphocyte proliferation assay,cytotoxic T lymphocytes and an indirect enzyme-linked immunosorbent assay (ELISA) for detecting IFN-γ were used to investigate cellular immune responses elicited by the combination treatment regime.Results:Compared with HUVEC and DOC single drug group,the number of lung metastasis in HUVEC-DOC combination treatment group was significantly decreased(P<0.05).In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes(CTLs) with a lytic activity against activated endothelium.IFN-γ in the serum of im-munized mice of the HUVEC-DOC combination treatment group was significantly higher than that in the other three groups(P<0.05). Conclusion:HUVEC vaccine with low dose of DOC could display synergistic anti-breast cancer effect.

Application of anti-angiogenic therapy in non-small cell lung cancer / 中国肿瘤临床

Non-small cell lung cancer (NSCLC) accounts for 85% of total cases of lung cancer, which has the highest incidence and mor-tality in China. Most patients with lung cancer present with advanced stage disease at the time of diagnosis. With the limited develop-ment of cytotoxic chemotherapy for NSCLC therapy, median overall survival in patients receiving platinum-based doublet chemothera-py has been less than one year in several trials. To date, anti-angiogenesis agents combined with chemotherapy, small molecule tyro-sine kinase inhibitors (TKI) and immune checkpoint inhibitors were commonly applied in NSCLC instead of purely chemotherapy, which makes a great breakthrough in NSCLC therapy. This review summarizes and discusses the application of anti-angiogenic therapy in ad-vanced NSCLC.

Methanolic extract of Euchelus asper exhibits in-ovo anti-angiogenic and in vitro anti-proliferative activities

BACKGROUND: The marine environment is a rich source of bioactive natural products. Many of the marine bioactive compounds have been derived successfully from molluscs. Euchelus asper is a marine mollusc which is commonly found in the intertidal rocky regions of the Mumbai coast. The present study was focused on evaluating the anti-angiogenic and anti- proliferative activities of methanolic extract of Euchelus asper (EAME). METHODS: The anti-angiogenic activity of EAME (50-800 µg/mL) was assessed by chick chorio-allantoic membrane (CAM) model wherein multiple parameters in the CAM blood vessels were analysed through morphometric and histo-logical investigations. In vitro testing of EAME (5-20 µg/mL) included its cytotoxicity against three different cancer cell lines, its effect on cell proliferation by wound healing assay as well as their relevant molecular mechanisms. Statistical analysis was carried out by two-tailed student's t test for two unpaired groups. RESULTS: Analysis of CAM revealed that the extract is effective in reducing the branching points of the 1st order blood vessels or capillaries of CAM. Histological analysis of CAM showed significant decrease in capillary plexus and compartmentalization along with increase in mesodermal blood vessels, thus establishing its anti-angiogenicity. Further, EAME exhibited moderate but significant cytotoxicity against A549 non-small cell lung carcinoma cell line. We also demonstrated that the cytotoxicity of EAME in A549 was associated with its apoptotic activity by subG1 phase arrest. Lastly, EAME significantly reduced A549 proliferation by reducing the expression of Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9). CONCLUSION: Overall, our study suggested that EAME has potential to inhibit tumour angiogenic and proliferative activity and may be a potential source for development of new anti-cancer pharmaceuticals.

Improved antitumor efficacy by combinationtreatment with recombined VEGF protein vaccineand cyclophosphamide in H22 hepatocellular carcinoma bearing-mice / 中国药理学通报

Aim To investigate the antitumor and antiangiogenic effects of combined low-dose cyclophosphamide(CTX)and recombined VEGF protein vaccine.Methods In this experiment,H22 hepatocellular carcinoma model was established in BALB/c mice.Mice were randomly divided into four groups: control group,CTX group(CTX),VEGF protein vaccine group(V2)and CTX plus V2 group(CTX+V2).The anti-tumor efficacy and antiangiogenic effect were investigated using a subcutaneous tumor model and an intradermal tumor model.Western blot and ELISAwere further adopted to detect the specific anti-VEGF antibody.Results CTX+V2 group displayed a lower tumor volume and tumor weight than either the single therapy group in the subcutaneous tumor model(P<005 vs V2,P<001 vs CTX).Meanwhile,CTX+V2 was more effective for antagonizing tumor-associated angiogenesis compared with either the single therapy(P<005 vs V2,P<001 vs CTX).After CTX+V2 immunization,high titer of anti-VEGF antibody was detected by ELISA and verified by Western blot.Conclusion The therapy of CTX combined with V2 has significant synergistic effect against H22 hepatocellular carcinoma.

Design, synthesis and antitumor activities of oxazolo[5, 4-d] pyrimidine derivatives / 中国药科大学学报

A series of oxazole[5,4-d] pyrimidine derivatives were designed and synthesized to discover novel compounds with antitumor activity.Compounds 8a-8m were synthesized using acetamidine hydrochloride as the start material.The structures of synthesized compounds were confirmed by IR,1H NMR,EI-MS and elemental analysis.The antiangiogenesis activities of the synthesized compounds were determined by MTT in human umbilical vein endothelial cell (HUVEC).The in vitro antitumor activities of the synthesized compounds were determined by MTT assay in A549,HepG2 and U251.Compounds 8c,8d,8g,8i and 8l were found to inhibit the proliferation of all the tested cell lines.Compound 8l exhibited noteworthy activities in A549,HepG2 and U251 cell lines with IC50value lower than the positive reference sunitinib,suggesting that compound 8l might be the promising antitumor agent for further investigation.

Rhythmic chemotherapy affects the growth of tumor cells by influencing the formation of blood vessels and the immune system / 实用肿瘤学杂志

Objective The objective of this study was to determine the effect of curative chemotherapy regimen on breast cancer cells and its mechanism.Methods A tumor-bearing mouse model was established and routine dose of capecitabine was given as a conventional chemotherapy group.Continuous low-dose capecitabine chemotherapy was used as a radiotherapy group and no chemotherapy was used as a control group.The expression of microvessel density(MVD),vascular endothelial growth factor(VEGF)and thrombospondin 1(TSP-1)were measured by flow cytometry.The percentage of myeloid-derived suppressor cells(MDSCs),NK cells and macrophages in the program was observed.The tumor size and blood leukocyte count were measured after chemotherapy.Results MVD and VEGF in the radiotherapy group were significantly decreased and TSP-1 was significantly increased in comparison with the conventional chemotherapy group(P0.05).However,the white blood cell count in the radiotherapy group was significantly higher than that in the conventional chemotherapy group(P<0.05).Conclusion Capecitabine chemotherapy at continuous low-dose inhibits neovascularization and adjusts the proportion of immune cells to suppress tumor formation.Thus,this chemotherapy could reduce side effects caused by chemotherapy and improve the quality of life.