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1.
J Ovarian Res ; 15(1): 56, 2022 May 10.
Article in English | MEDLINE | ID: mdl-35538489

ABSTRACT

Multifaceted functions of the so-called "oncogene" Wip1 have been reported in a previous study, while its actual role remains to be explored in serous ovarian cancer (SOC). In this study, by performing bioinformatic analysis with a public database and immunohistochemical staining of Wip1 in tumour tissue from SOC, we concluded that decreased expression of Wip1 was associated with a higher rate of tumour metastasis and platinum-based therapy resistance and increased ascites volume, which led to poorer prognosis in SOC patients. We also found that overexpression of Wip1 in SKOV3 cells decreased the levels of several cytokines, including VEGF, by secretome profiling analysis, and Wip1 overexpression suppressed angiogenesis both in vitro and in vivo. Mechanistic studies indicated that overexpression of Wip1 decreased the expression of VEGF at both the protein and mRNA levels and that the inhibitory effect was mediated by dephosphorylation of STAT3 at Ser727. Our study uncovered the role of Wip1 in SOC and provides a novel therapeutic strategy for suppressing angiogenesis.


Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Protein Phosphatase 2C , STAT3 Transcription Factor , Vascular Endothelial Growth Factor A , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/metabolism , Cell Line, Tumor , Cystadenocarcinoma, Serous/blood supply , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/metabolism , Female , Humans , Neovascularization, Pathologic/genetics , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/pathology , Protein Phosphatase 2C/genetics , Protein Phosphatase 2C/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
2.
Expert Opin Pharmacother ; 21(13): 1579-1590, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32552175

ABSTRACT

Angiogenesis inhibitors have clearly shown activity in ovarian cancer in various settings; however, preliminary data did not reflect significant survival benefit. Bevacizumab has been extensively studied and is approved for use in ovarian malignancy. However, the efficacy of bevacizumab is modest and most treated patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Newer therapies are being evaluated and their role of these newer therapies is upcoming and promising. Recent research focuses on the role of this drug group in frontline, maintenance and recurrent settings. Combination of PARP inhibitors with angiogenesis inhibitors has recently shown to improved survival rates. Potential strategies need to be devised for selecting patients most likely to benefit from such therapy.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Neovascularization, Pathologic/drug therapy , Ovarian Neoplasms/drug therapy , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/mortality , Clinical Trials as Topic , Female , Humans , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/mortality , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Treatment Outcome
3.
Clin Exp Metastasis ; 37(2): 293-304, 2020 04.
Article in English | MEDLINE | ID: mdl-32008138

ABSTRACT

Most women with epithelial ovarian cancer (EOC) suffer from peritoneal carcinomatosis upon first clinical presentation. Extensive peritoneal carcinomatosis has a poor prognosis and its pathophysiology is not well understood. Although treatment with systemic intravenous chemotherapy is often initially successful, peritoneal recurrences occur regularly. We hypothesized that insufficient or poorly-perfused microvasculature may impair the therapeutic efficacy of systemic intravenous chemotherapy but may also limit expansive and invasive growth characteristic of peritoneal EOC metastases. In 23 patients with advanced EOC or suspicion thereof, we determined the angioarchitecture and perfusion of the microvasculature in peritoneum and in peritoneal metastases using incident dark field (IDF) imaging. Additionally, we performed immunohistochemical analysis and 3-dimensional (3D) whole tumor imaging using light sheet fluorescence microscopy of IDF-imaged tissue sites. In all metastases, microvasculature was present but the angioarchitecture was chaotic and the vessel density and perfusion of vessels was significantly lower than in unaffected peritoneum. Immunohistochemical analysis showed expression of vascular endothelial growth factor and hypoxia inducible factor 1α, and 3D imaging demonstrated vascular continuity between metastases and the vascular network of the peritoneum beneath the elastic lamina of the peritoneum. We conclude that perfusion of the microvasculature within metastases is limited, which may cause hypoxia, affect the behavior of EOC metastases on the peritoneum and limit the response of EOC metastases to systemic treatment.


Subject(s)
Carcinoma, Ovarian Epithelial/blood supply , Microvessels/diagnostic imaging , Ovarian Neoplasms/therapy , Peritoneal Neoplasms/blood supply , Peritoneum/pathology , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial/secondary , Carcinoma, Ovarian Epithelial/therapy , Cell Hypoxia , Chemotherapy, Adjuvant , Cytoreduction Surgical Procedures , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/analysis , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Imaging, Three-Dimensional , Immunohistochemistry , Microvessels/pathology , Middle Aged , Neoadjuvant Therapy , Ovarian Neoplasms/pathology , Ovariectomy , Ovary/pathology , Ovary/surgery , Peritoneal Neoplasms/prevention & control , Peritoneal Neoplasms/secondary , Peritoneum/blood supply , Prospective Studies , Treatment Outcome , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor A/metabolism
4.
Gynecol Oncol ; 156(3): 545-551, 2020 03.
Article in English | MEDLINE | ID: mdl-31932108

ABSTRACT

OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. RESULTS: Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Ovarian Epithelial/blood , Carcinoma, Ovarian Epithelial/blood supply , Cardiotoxicity/etiology , Dose-Response Relationship, Drug , Female , Humans , Indazoles , Neoplasm Recurrence, Local , Neovascularization, Pathologic/blood , Neovascularization, Pathologic/drug therapy , Ovarian Neoplasms/blood , Ovarian Neoplasms/blood supply , Progression-Free Survival , Pyrimidines/adverse effects , Stilbenes/administration & dosage , Stilbenes/adverse effects , Sulfonamides/adverse effects , Survival Rate
5.
Br J Cancer ; 122(3): 361-371, 2020 02.
Article in English | MEDLINE | ID: mdl-31772325

ABSTRACT

BACKGROUND: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. METHODS: In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). RESULTS: ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. CONCLUSION: FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.


Subject(s)
Carcinoma, Ovarian Epithelial/pathology , Cell Differentiation/drug effects , Neoplastic Stem Cells/drug effects , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/pathology , Peptides/pharmacology , Tacrolimus Binding Proteins , Animals , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/metabolism , Cell Line, Tumor , Female , Humans , Hyaluronan Receptors/drug effects , Hyaluronan Receptors/metabolism , In Vitro Techniques , Interleukin-6/metabolism , Mice , Mice, SCID , Neovascularization, Pathologic/metabolism , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/metabolism , STAT3 Transcription Factor/drug effects , STAT3 Transcription Factor/metabolism , Signal Transduction , Tacrolimus Binding Proteins/drug effects , Tacrolimus Binding Proteins/metabolism , Xenograft Model Antitumor Assays
6.
Int J Oncol ; 55(6): 1296-1312, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31638182

ABSTRACT

Angiogenesis has an important role in tumour cell growth and metastasis. Anisomycin has been shown to inhibit tumour cell growth. However, whether anisomycin can inhibit angiogenesis of tumours has not been reported. The present study demonstrated that there was a positive correlation between tumour angiogenesis and the number of CD44+/CD133+ serous human ovarian cancer stem cells (HuOCSCs). Subsequently, it was confirmed that anisomycin significantly inhibited the proliferation, invasion, tumorigenic ability and tumour angiogenesis of HuOCSCs. Gene expression profiling by cDNA microarrays revealed that the expression levels of vascular endothelial cell markers, platelet­derived growth factors, Notch pathway components and 27 tumour angiogenesis­related genes were significantly decreased in the anisomycin­treated group compared with the control group. Further experiments demonstrated that the expression levels of endogenous long non­coding RNA (lncRNA) maternally expressed 3 (Meg3) were significantly decreased in anisomycin­treated HuOCSCs, whereas the expression levels of microRNA (miR)­421 were significantly increased. The results of luciferase reporter assays indicated that, when miR­421 was overexpressed in cells, the luciferase activities of wild­type platelet derived growth factor receptor α (PDGFRA) 3' untranslated region and Meg3 reporter plasmids were significantly decreased. Overexpression of miR­421 in HuOCSCs significantly enhanced the anisomycin­mediated inhibition of HuOCSC proliferation. Taken together, the present results demonstrated that anisomycin inhibited the activation downstream of the Notch1 pathway by attenuating the molecular sponge effect of the lncRNA­Meg3/miR­421/PDGFRA axis, ultimately inhibiting angiogenesis, proliferation and invasion in ovarian cancer cells.


Subject(s)
Anisomycin/pharmacology , Carcinoma, Ovarian Epithelial/drug therapy , Gene Expression Regulation, Neoplastic/drug effects , Neovascularization, Pathologic/drug therapy , Ovarian Neoplasms/drug therapy , 3' Untranslated Regions/genetics , Animals , Anisomycin/therapeutic use , Carcinogenesis/drug effects , Carcinogenesis/genetics , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/pathology , Cell Proliferation/drug effects , Cell Proliferation/genetics , Drug Screening Assays, Antitumor , Embryo, Nonmammalian , Female , Humans , Mice , MicroRNAs/agonists , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Neoplastic Stem Cells , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Neovascularization, Physiologic/drug effects , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ovary/pathology , Primary Cell Culture , RNA, Long Noncoding/metabolism , Receptor, Platelet-Derived Growth Factor alpha/genetics , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Zebrafish
7.
Oncogene ; 38(33): 6095-6108, 2019 08.
Article in English | MEDLINE | ID: mdl-31289363

ABSTRACT

Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach. However, effective miRNA-delivery systems are needed for such approaches to be successful. In this study, miRNA profiling of patient data sets, along with in vitro and in vivo experiments, revealed that miR-204-5p could promote angiogenesis in ovarian tumors through THBS1. By binding with scavenger receptor class B type 1 (SCARB1), reconstituted high-density lipoprotein-nanoparticles (rHDL-NPs) were effective in delivering miR-204-5p inhibitor (miR-204-5p-inh) to tumor sites to suppress tumor growth. These results offer a new understanding of miR-204-5p in regulating tumor angiogenesis.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/genetics , MicroRNAs , Neovascularization, Pathologic/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Angiogenesis Inhibitors/pharmacology , Animals , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , Mice , Mice, Nude , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , Molecular Targeted Therapy/methods , Neovascularization, Pathologic/drug therapy , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/pathology , RNA, Small Interfering/pharmacology , RNA, Small Interfering/therapeutic use , Xenograft Model Antitumor Assays
8.
BMC Cancer ; 19(1): 564, 2019 Jun 11.
Article in English | MEDLINE | ID: mdl-31185938

ABSTRACT

BACKGROUND: Pre-operative discrimination of malignant from benign adnexal masses is crucial for planning additional imaging, preparation, surgery and postoperative care. This study aimed to define key ultrasound and clinical variables and develop a predictive model for calculating preoperative ovarian tumor malignancy risk in a gynecologic oncology referral center. We compared our model to a subjective ultrasound assessment (SUA) method and previously described models. METHODS: This prospective, single-center observational study included consecutive patients. We collected systematic ultrasound and clinical data, including cancer antigen 125, D-dimer (DD) levels and platelet count. Histological examinations served as the reference standard. We performed univariate and multivariate regressions, and Bayesian information criterion (BIC) to assess the optimal model. Data were split into 2 subsets: training, for model development (190 observations) and testing, for model validation (n = 100). RESULTS: Among 290 patients, 52% had malignant disease, including epithelial ovarian cancer (72.8%), metastatic disease (14.5%), borderline tumors (6.6%), and non-epithelial malignancies (4.6%). Significant variables were included into a multivariate analysis. The optimal model, included three independent factors: solid areas, the color score, and the DD level. Malignant and benign lesions had mean DD values of 2.837 and 0.354 µg/ml, respectively. We transformed established formulae into a web-based calculator ( http://gin-onc-calculators.com/gynonc.php ) for calculating the adnexal mass malignancy risk. The areas under the curve (AUCs) for models compared in the testing set were: our model (0.977), Simple Rules risk calculation (0.976), Assessment of Different NEoplasias in the adneXa (ADNEX) (0.972), Logistic Regression 2 (LR2) (0.969), Risk of Malignancy Index (RMI) 4 (0.932), SUA (0.930), and RMI3 (0.912). CONCLUSIONS: Two simple ultrasound predictors and the DD level (also included in a mathematical model), when used by gynecologist oncologist, discriminated malignant from benign ovarian lesions as well or better than other more complex models and the SUA method. These parameters (and the model) may be clinically useful for planning adequate management in the cancer center. The model needs substantial validation.


Subject(s)
Adnexa Uteri/pathology , Adnexal Diseases/diagnosis , Carcinoma, Ovarian Epithelial/diagnosis , Models, Theoretical , Risk Assessment/methods , Adult , Aged , Area Under Curve , Bayes Theorem , CA-125 Antigen/blood , Carcinoma, Ovarian Epithelial/blood supply , Diagnosis, Differential , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Logistic Models , Middle Aged , Platelet Count , Prospective Studies , ROC Curve , Regional Blood Flow , Sensitivity and Specificity , Tumor Burden , Ultrasonography, Doppler
9.
Hematol Oncol Clin North Am ; 32(6): 1041-1055, 2018 12.
Article in English | MEDLINE | ID: mdl-30390759

ABSTRACT

Epithelial ovarian cancer remains the most lethal gynecologic cancers with a 5-year survival rate of less than 50%. Cytotoxic combinations are associated with incremental toxicity, leading to interest in evaluating cytotoxic/biologic combinations with improved therapeutic ratios. Angiogenesis is critical to the normal physiology of the gynecologic tract and a novel drug target. Current data suggests antiangiogenics should be considered a critical component of epithelial ovarian cancer treatment. Given the serious adverse event of gastrointestinal perforation/fistula in advanced disease, priority should be given to front-line treatment. Active investigation continues in the development of novel combinations with other biologics.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial , Neovascularization, Pathologic , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/metabolism , Carcinoma, Ovarian Epithelial/pathology , Female , Humans , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology
10.
Hematol Oncol Clin North Am ; 32(6): 965-982, 2018 12.
Article in English | MEDLINE | ID: mdl-30390768

ABSTRACT

Most women with advanced epithelial ovarian cancer will experience many episodes of recurrent disease with progressively shorter disease-free intervals. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Enormous progress has been made in the management of this disease, and new targeted treatments such as antiangiogenic drugs, poly(adenosine diphosphate-ribose) polymerase inhibitors, and immune checkpoint inhibitors offer potential for improved survival. A variety of combination strategies are being evaluated to leverage these agents. The role of secondary cytoreduction remains a topic of active investigation.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial , Cytoreduction Surgical Procedures/methods , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/blood supply , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/metabolism , Carcinoma, Ovarian Epithelial/therapy , Female , Humans , Neoplasm Recurrence, Local , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/therapy
11.
J Biol Inorg Chem ; 23(6): 939-947, 2018 08.
Article in English | MEDLINE | ID: mdl-30014256

ABSTRACT

Arsenic trioxide (As2O3) induces cell apoptosis and reduces the invasive and metastatic activities in various cancer types. However, the role of As2O3 in ovarian cancer angiogenesis remains unclear. In this study, we investigated the role of As2O3 in ovarian cancer angiogenesis and found that a low concentration of As2O3 causes no effects on epithelial ovarian cancer cell viability or apoptosis. Moreover, we found that As2O3-treated epithelial ovarian cancer cells demonstrate a reduced tube formation of endothelial cells in Matrigel. In addition, As2O3-treated epithelial ovarian cancer cells show a decreased VEGFA, VEGFR2 and CD31 mRNA expression. As per the underlying mechanisms involved in As2O3 treatment, we found that As2O3 inhibits VEGFA and VEGFR2 expression that thereby inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway. This leads to a suppression in both VEGFA synthesis and angiogenesis-related gene expression. A decreased VEGFA synthesis and secretion also inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway in human umbilical vein endothelial cells (HUVECs). In summary, our results may provide strategies for the use of As2O3 in the prevention of tumor angiogenesis.


Subject(s)
Apoptosis , Arsenic Trioxide/pharmacology , Carcinoma, Ovarian Epithelial/blood supply , Neovascularization, Pathologic/prevention & control , Ovarian Neoplasms/blood supply , Arsenic Trioxide/administration & dosage , Carcinoma, Ovarian Epithelial/metabolism , Carcinoma, Ovarian Epithelial/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Female , Humans , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , RNA, Messenger/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism
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