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Byrne A, Le D, Sereti K, Menon H, Vaidya S, Patel N, Lund J, Xavier-Magalhães A, Shi M, Liang Y, Sterne-Weiler T, Modrusan Z, Stephenson W. Single-cell long-read targeted sequencing reveals transcriptional variation in ovarian cancer. Nat Commun 2024; 15:6916. [PMID: 39134520 PMCID: PMC11319652 DOI: 10.1038/s41467-024-51252-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 07/31/2024] [Indexed: 08/15/2024] Open
Abstract
Single-cell RNA sequencing predominantly employs short-read sequencing to characterize cell types, states and dynamics; however, it is inadequate for comprehensive characterization of RNA isoforms. Long-read sequencing technologies enable single-cell RNA isoform detection but are hampered by lower throughput and unintended sequencing of artifacts. Here we develop Single-cell Targeted Isoform Long-Read Sequencing (scTaILoR-seq), a hybridization capture method which targets over a thousand genes of interest, improving the median number of on-target transcripts per cell by 29-fold. We use scTaILoR-seq to identify and quantify RNA isoforms from ovarian cancer cell lines and primary tumors, yielding 10,796 single-cell transcriptomes. Using long-read variant calling we reveal associations of expressed single nucleotide variants (SNVs) with alternative transcript structures. Phasing of SNVs across transcripts enables the measurement of allelic imbalance within distinct cell populations. Overall, scTaILoR-seq is a long-read targeted RNA sequencing method and analytical framework for exploring transcriptional variation at single-cell resolution.
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Affiliation(s)
- Ashley Byrne
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Daniel Le
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Kostianna Sereti
- Department of Discovery Oncology, Genentech, South San Francisco, CA, USA
| | - Hari Menon
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Samir Vaidya
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Neha Patel
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Jessica Lund
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Ana Xavier-Magalhães
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Minyi Shi
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Yuxin Liang
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
| | - Timothy Sterne-Weiler
- Department of Discovery Oncology, Genentech, South San Francisco, CA, USA
- Department of Oncology Bioinformatics, Genentech, South San Francisco, CA, USA
| | - Zora Modrusan
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA.
| | - William Stephenson
- Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA.
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Abstract
Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related mortality in the developed world. EOC is a heterogeneous disease represented by several histological and molecular subtypes. Therefore, exploration of relevant preclinical animal models that consider the heterogenic nature of EOC is of great importance for the development of novel therapeutic strategies that can be translated clinically to combat this devastating disease. In this review, we discuss recent progress in the development of preclinical mouse models for EOC study as well as their advantages and limitations.
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Affiliation(s)
- Sergey Karakashev
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Ru-Gang Zhang
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. E-mail:
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3
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Zhang Y, Li C, Qin Y, Cepparulo P, Millman M, Chopp M, Kemper A, Szalad A, Lu X, Wang L, Zhang ZG. Small extracellular vesicles ameliorate peripheral neuropathy and enhance chemotherapy of oxaliplatin on ovarian cancer. J Extracell Vesicles 2021; 10:e12073. [PMID: 33728031 PMCID: PMC7931803 DOI: 10.1002/jev2.12073] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 01/07/2021] [Accepted: 02/13/2021] [Indexed: 12/17/2022] Open
Abstract
There are no effective treatments for chemotherapy induced peripheral neuropathy (CIPN). Small extracellular vesicles (sEVs) facilitate intercellular communication and mediate nerve function and tumour progression. We found that the treatment of mice bearing ovarian tumour with sEVs derived from cerebral endothelial cells (CEC-sEVs) in combination with a chemo-drug, oxaliplatin, robustly reduced oxaliplatin-induced CIPN by decreasing oxaliplatin-damaged myelination and nerve fibres of the sciatic nerve and significantly amplified chemotherapy of oxaliplatin by reducing tumour size. The combination therapy substantially increased a set of sEV cargo-enriched miRNAs, but significantly reduced oxaliplatin-increased proteins in the sciatic nerve and tumour tissues. Bioinformatics analysis revealed the altered miRNAs and proteins formed two distinct networks that regulate neuropathy and tumour growth, respectively. Intravenously administered CEC-sEVs were internalized by axons of the sciatic nerve and cancer cells. Reduction of CEC-sEV cargo miRNAs abolished the effects of CEC-sEVs on oxaliplatin-inhibited axonal growth and on amplification of the anti-cancer effect in ovarian cancer cells, suggesting that alterations in the networks of miRNAs and proteins in recipient cells contribute to the therapeutic effect of CEC-sEVs on CIPN. Together, the present study demonstrates that CEC-sEVs suppressed CIPN and enhanced chemotherapy of oxaliplatin in the mouse bearing ovarian tumour.
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Affiliation(s)
- Yi Zhang
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Chao Li
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Yi Qin
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | | | | | - Michael Chopp
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
- Department of PhysicsOakland UniversityRochesterMichiganUSA
| | - Amy Kemper
- Department of PathologyHenry Ford Health SystemDetroitMichiganUSA
| | - Alexandra Szalad
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Xuerong Lu
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Lei Wang
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Zheng Gang Zhang
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
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4
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Dai L, Song K, Di W. Adipocytes: active facilitators in epithelial ovarian cancer progression? J Ovarian Res 2020; 13:115. [PMID: 32967712 PMCID: PMC7513299 DOI: 10.1186/s13048-020-00718-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/14/2020] [Indexed: 12/11/2022] Open
Abstract
There is growing evidence that adipocytes play important roles in the progression of multiple cancers. Moreover, in obesity, adipocytes alter their original functions and contribute to the metabolic and inflammatory changes of adipose tissue microenvironment, which can further enhance tumor development. At present, the roles of adipocytes in the pathogenesis of epithelial ovarian cancer (EOC) are far from being fully elucidated. Herein, we summarized the recent advances in understanding the roles of adipocytes in EOC progression. Adipocytes, close neighbors of EOC tissue, promote EOC growth, invasion, metastasis and angiogenesis through adipokine secretion, metabolic remodeling and immune microenvironment modulation. Moreover, adipocytes are important therapeutic targets and may work as useful anticancer drug delivery depot for EOC treatment. Furthermore, adipocytes also act as a therapeutic obstacle for their involvement in EOC treatment resistance. Hence, better characterization of the adipocytes in EOC microenvironment and the crosstalk between adipocytes and EOC cells may provide insights into EOC progression and suggest novel therapeutic opportunities.
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Affiliation(s)
- Lan Dai
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. .,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Keqi Song
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wen Di
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. .,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. .,State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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5
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Komura N, Mabuchi S, Shimura K, Kawano M, Matsumoto Y, Kimura T. Significance of Pretreatment C-Reactive Protein, Albumin, and C-Reactive Protein to Albumin Ratio in Predicting Poor Prognosis in Epithelial Ovarian Cancer Patients. Nutr Cancer 2020; 73:1357-1364. [PMID: 32835520 DOI: 10.1080/01635581.2020.1798479] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
To investigate the prognostic significance of pretreatment C-reactive protein (CRP), albumin, and the CRP to albumin ratio (CRP/Alb) in epithelial ovarian cancer (EOC) patients. Clinical data from 308 EOC patients between April 2007 and March 2016 were collected and retrospectively reviewed. The cutoff values for CRP, albumin, and CRP/Alb were defined by receiver operating characteristics (ROC) analyses. Univariate or multivariate analysis was conducted to evaluate the prognostic significance of these factors for disease-specific survival. The cutoff values for CRP, albumin, and CRP/Alb were 0.76, 3.8, and 0.048 by ROC analysis, respectively. Cox regression analyses demonstrated that an elevated CRP/Alb is an independent predictor of short disease-specific survival irrespective of clinical stage or optimal surgery rate. When examined according to clinical stage, elevated CRP/Alb was associated with short disease-specific survival in both early-stage and advanced-stage patients. Cox regression analyses demonstrated that an elevated CRP, but not lower albumin, is also an independent predictor of short disease-specific survival. When two prognosticators were compared, CRP/Alb was found to be superior to CRP for predicting disease-specific survival in EOC patients. Pretreatment elevated CRP/Alb is a predictor of shorter survival in EOC patients regardless of clinical stage.
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Affiliation(s)
- Naoko Komura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Seiji Mabuchi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kotaro Shimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Mahiru Kawano
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuri Matsumoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Klymenko Y, Wates RB, Weiss-Bilka H, Lombard R, Liu Y, Campbell L, Kim O, Wagner D, Ravosa MJ, Stack MS. Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates. Dis Model Mech 2018; 11:dmm034199. [PMID: 30254133 PMCID: PMC6176988 DOI: 10.1242/dmm.034199] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/29/2018] [Indexed: 12/12/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. EOC dissemination is predominantly via direct extension of cells and multicellular aggregates (MCAs) into the peritoneal cavity, which adhere to and induce retraction of peritoneal mesothelium and proliferate in the submesothelial matrix to generate metastatic lesions. Metastasis is facilitated by the accumulation of malignant ascites (500 ml to >2 l), resulting in physical discomfort and abdominal distension, and leading to poor prognosis. Although intraperitoneal fluid pressure is normally subatmospheric, an average intraperitoneal pressure of 30 cmH2O (22.1 mmHg) has been reported in women with EOC. In this study, to enable experimental evaluation of the impact of high intraperitoneal pressure on EOC progression, two new in vitro model systems were developed. Initial experiments evaluated EOC MCAs in pressure vessels connected to an Instron to apply short-term compressive force. A Flexcell Compression Plus system was then used to enable longer-term compression of MCAs in custom-designed hydrogel carriers. Results show changes in the expression of genes related to epithelial-mesenchymal transition as well as altered dispersal of compressed MCAs on collagen gels. These new model systems have utility for future analyses of compression-induced mechanotransduction and the resulting impact on cellular responses related to intraperitoneal metastatic dissemination.This article has an associated First Person interview with the first authors of the paper.
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Affiliation(s)
- Yuliya Klymenko
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
| | - Rebecca B Wates
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Holly Weiss-Bilka
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Rachel Lombard
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
| | - Yueying Liu
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
| | - Leigh Campbell
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
| | - Oleg Kim
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
- Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA
- Department of Mathematics, University of California, Riverside, CA 92521, USA
| | - Diane Wagner
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Matthew J Ravosa
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
| | - M Sharon Stack
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
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7
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Zhao S, Zhang Y, Wang L, Yang L, Zou L, Gao F. Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap: a new treatment option for glioma. Cancer Biol Ther 2018; 20:65-72. [PMID: 30136881 PMCID: PMC6343700 DOI: 10.1080/15384047.2018.1504725] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background: Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap (AAV2-VEGF-Trap) has been reported to inhibit the growth of primary tumor as well as distant metastasis in 4T1 metastatic breast cancer models. The aim of this study was to investigate the inhibiting efficacy of AAV2-VEGF-Trap for glioma. Methods: The intracranial transplanted model of glioma in rats was established. They were treated with AAV2-VEGF-Trap, bevacizumab (BEV), temozolomide (TMZ), TMZ combined with AAV2-VEGF-Trap, TMZ combined with BEV and the control group, respectively. A 7.0 Tesla magnetic resonance (MR) was used to assess the tumor volumes and obtain the apparent diffusion coefficient (ADC) values. Immunohistochemical and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to evaluate the effects on tumor angiogenesis, proliferation and apoptosis. Results: The combination of TMZ with AAV2-VEGF-Trap or BEV showed greater tumor growth inhibition than the other groups, and the ADC values in these two groups were larger than that of the control group. The decreased microvessel density in treatment groups which contain AAV2-VEGF-Trap or BEV was observed. The reduced proliferation activity in groups containing TMZ and increased apoptotic tumor cells in TMZ combined with AAV2-VEGF-Trap group and TMZ combined with BEV group were detected. In addition, there were no differences in antitumor effect, ADC values, Ki-67 and CD31 staining and apoptosis analysis between the two combined therapy groups. Conclusion: AAV2-VEGF-Trap has an obvious anti-angiogenic effect and inhibits the growth of glioma just by a single intravenous injection, which is similar to BEV. Moreover, there is a synergistic antitumor effect between AAV2-VEGF-Trap and TMZ.
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Affiliation(s)
- Shengnan Zhao
- a Department of Medical Oncology , Cancer Center , West China Hospital of Sichuan University , Chengdu, China
| | - Yakun Zhang
- a Department of Medical Oncology , Cancer Center , West China Hospital of Sichuan University , Chengdu, China.,b Department of Oncology , the Affiliated Hospital of North Sichuan Medical College , Nanchong , China
| | - Lei Wang
- c Department of Radiology , West China Hospital of Sichuan University , Chengdu , China
| | - Li Yang
- d State Key Laboratory of Biotherapy , West China Hospital of Sichuan University , Chengdu , China
| | - Liqun Zou
- a Department of Medical Oncology , Cancer Center , West China Hospital of Sichuan University , Chengdu, China
| | - Fabao Gao
- c Department of Radiology , West China Hospital of Sichuan University , Chengdu , China
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8
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Áyen Á, Jiménez Martínez Y, Marchal JA, Boulaiz H. Recent Progress in Gene Therapy for Ovarian Cancer. Int J Mol Sci 2018; 19:ijms19071930. [PMID: 29966369 PMCID: PMC6073662 DOI: 10.3390/ijms19071930] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 06/26/2018] [Accepted: 06/27/2018] [Indexed: 01/06/2023] Open
Abstract
Ovarian cancer is the most lethal gynecological malignancy in developed countries. This is due to the lack of specific symptoms that hinder early diagnosis and to the high relapse rate after treatment with radical surgery and chemotherapy. Hence, novel therapeutic modalities to improve clinical outcomes in ovarian malignancy are needed. Progress in gene therapy has allowed the development of several strategies against ovarian cancer. Most are focused on the design of improved vectors to enhance gene delivery on the one hand, and, on the other hand, on the development of new therapeutic tools based on the restoration or destruction of a deregulated gene, the use of suicide genes, genetic immunopotentiation, the inhibition of tumour angiogenesis, the alteration of pharmacological resistance, and oncolytic virotherapy. In the present manuscript, we review the recent advances made in gene therapy for ovarian cancer, highlighting the latest clinical trials experience, the current challenges and future perspectives.
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Affiliation(s)
- Ángela Áyen
- Department of Human Anatomy and Embryology, University of Granada, 18016 Granada, Spain.
| | - Yaiza Jiménez Martínez
- Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, 18016 Granada, Spain.
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, 18016 Granada, Spain.
| | - Juan A Marchal
- Department of Human Anatomy and Embryology, University of Granada, 18016 Granada, Spain.
- Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, 18016 Granada, Spain.
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, 18016 Granada, Spain.
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, 18016 Granada, Spain.
| | - Houria Boulaiz
- Department of Human Anatomy and Embryology, University of Granada, 18016 Granada, Spain.
- Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, 18016 Granada, Spain.
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, 18016 Granada, Spain.
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, 18016 Granada, Spain.
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Combined Gene Therapy Using AdsVEGFR2 and AdsTie2 With Chemotherapy Reduces the Growth of Human Ovarian Cancer and Formation of Ascites in Mice. Int J Gynecol Cancer 2018; 27:879-886. [PMID: 28498260 DOI: 10.1097/igc.0000000000000973] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer. METHODS An intraperitoneal human ovarian cancer xenograft model in nude mice (n = 44) was used in this study. Gene therapy was given intravenously when the presence of sizable tumors was confirmed in magnetic resonance imaging. The study groups were as follows: AdCMV as a control (group I), AdCMV with chemotherapy (group II), AdsVEGFR2 and AdsTie2 (group III), and AdsVEGFR2 and AdsTie2 with chemotherapy (group IV). Antitumor effectiveness was assessed by overall tumor growth, ascites, immunohistochemistry, microvessel density, and sequential magnetic resonance imaging analyses. RESULTS AdsVEGFR2 and AdsTie2 gene therapy (group III) significantly reduced tumor weights as compared with group II (P = 0.007). Accumulation of ascites was significantly reduced when the mice were treated with AdsVEGFR2 and AdsTie2 gene therapy or with combined gene therapy and chemotherapy as compared with controls (P = 0.029 and P = 0.010, respectively). Vascular endothelial growth factor and Ang2 levels in ascites fluid were elevated after the gene therapy. CONCLUSIONS Combined inhibition of VEGF/VEGFR2 and Ang/Tie2 pathways provided efficient therapy for ovarian cancer in mice. In addition, antiangiogenic gene therapy has potential as a treatment for the accumulation of ascites.
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10
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Weidle UH, Birzele F, Kollmorgen G, Nopora A. Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis. Cancer Genomics Proteomics 2018; 15:1-15. [PMID: 29275359 PMCID: PMC5822180 DOI: 10.21873/cgp.20061] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/09/2017] [Accepted: 10/17/2017] [Indexed: 02/06/2023] Open
Abstract
Treatment of disseminated epithelial ovarian cancer (EOC) is an unmet medical need. Therefore, the identification along with preclinical and clinical validation of new targets is an issue of high importance. In this review we focus on microRNAs that mediate metastasis of EOC. We summarize up-regulated metastasis-promoting and down-regulated metastasis-suppressing microRNAs. We focus on preclinical in vitro and in vivo functions as well as their metastasis-related clinical correlations. Finally, we outline modalities for therapeutic intervention and critical issues of microRNA-based therapeutics in the context of metastatic EOC.
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Affiliation(s)
- Ulrich H Weidle
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Fabian Birzele
- Roche Innovation Center Basel, F. Hofman La Roche, Basel, Switzerland
| | - Gwen Kollmorgen
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Adam Nopora
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
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11
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Cavaco M, Goncalves J. Interactions Between Therapeutic Proteins and Small Molecules: The Shared Role of Perpetrators and Victims. Clin Pharmacol Ther 2017; 102:649-661. [PMID: 28002637 DOI: 10.1002/cpt.605] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 11/21/2016] [Accepted: 12/12/2016] [Indexed: 12/19/2022]
Abstract
Therapeutic proteins (TPs) are becoming increasingly important as therapeutic agents. A consequence of expanding their clinical indications is coadministration with well-established small-molecule drugs (sMDs), which could lead to unpredictable effects. According to the existing regulatory guidance, the development of an sMD includes the evaluation of potential drug-drug interactions (DDIs). For TPs, only a few drug interaction studies have been published. Limited clinically relevant models, long half-lives, and complex elimination pathways are among the associated difficulties.
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Affiliation(s)
- M Cavaco
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - J Goncalves
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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12
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Falcon BL, Chintharlapalli S, Uhlik MT, Pytowski B. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacol Ther 2016; 164:204-25. [PMID: 27288725 DOI: 10.1016/j.pharmthera.2016.06.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.
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13
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Huang J, Hu W, Hu L, Previs RA, Dalton HJ, Yang XY, Sun Y, McGuire M, Rupaimoole R, Nagaraja AS, Kang Y, Liu T, Nick AM, Jennings NB, Coleman RL, Jaffe RB, Sood AK. Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth. Mol Cancer Ther 2016; 15:1344-52. [PMID: 27009216 PMCID: PMC4893925 DOI: 10.1158/1535-7163.mct-15-0144] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 02/26/2016] [Indexed: 12/15/2022]
Abstract
Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344-52. ©2016 AACR.
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Affiliation(s)
- Jie Huang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Limin Hu
- Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California
| | - Rebecca A Previs
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Heather J Dalton
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiao-Yun Yang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yunjie Sun
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael McGuire
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rajesha Rupaimoole
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Archana S Nagaraja
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yu Kang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tao Liu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alpa M Nick
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nicholas B Jennings
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert L Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert B Jaffe
- Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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14
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Meyer L, Suidan R, Sun C, Westin S, Coleman RL, Mills GB. The management of malignant ascites and impact on quality of life outcomes in women with ovarian cancer. EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE 2016; 1:231-238. [PMID: 30906877 PMCID: PMC6425954 DOI: 10.1080/23809000.2016.1185369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Malignant ascites is one of the most common sequela of epithelial ovarian cancer. It causes significant symptoms and can have a detrimental impact on patient quality of life, especially in women with recurrent ovarian cancer. The management of symptomatic ascites consists of both mechanical treatments that aim to drain the peritoneal cavity, and medical therapies that prevent and diminish the development of ascites. Mechanical options include serial paracentesis, peritoneal catheters, and peritoneovenous shunts. Pharmaceutical treatments include diuretics, angiogenesis inhibitors, and other targeted agents. There is a perception, without formal analysis, that intractable ascites is less common in the taxane era of therapy. In this review paper, we highlight current and emerging therapeutic strategies, complications and contraindications, and their effects on patient quality of life.
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Affiliation(s)
- Larissa Meyer
- The University of Texas MD Anderson Cancer Center, Houston Texas, United States
| | - Rudy Suidan
- The University of Texas MD Anderson Cancer Center, Houston Texas, United States
| | - Charlotte Sun
- The University of Texas MD Anderson Cancer Center, Houston Texas, United States
| | - Shannon Westin
- The University of Texas MD Anderson Cancer Center, Houston Texas, United States
| | - Robert L Coleman
- The University of Texas MD Anderson Cancer Center, Houston Texas, United States
| | - Gordon B Mills
- The University of Texas MD Anderson Cancer Center, Houston Texas, United States
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15
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Giampieri R, Caporale M, Pietrantonio F, De Braud F, Negri FV, Giuliani F, Pusceddu V, Demurtas L, Restivo A, Fontanella C, Aprile G, Cascinu S, Scartozzi M. Second-line angiogenesis inhibition in metastatic colorectal cancer patients: Straightforward or overcrowded? Crit Rev Oncol Hematol 2016; 100:99-106. [PMID: 26907512 DOI: 10.1016/j.critrevonc.2016.02.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 12/26/2015] [Accepted: 02/10/2016] [Indexed: 02/06/2023] Open
Abstract
Although the number of therapeutic options targeting tumour angiogenesis is becoming increasingly relevant, the question of the optimal choice for second-line anti-angiogenic inhibition in combination with chemotherapy for metastatic colorectal cancer patients remains largely unanswered. In fact the lack of head to head comparison between consolidated options such as bevacizumab and new treatment alternatives such as aflibercept and ramucirumab makes the selection in the clinical practice challenging, particularly when the patient has already received an anti-angiogenic-based combination up-front. In the following pages we described the biological scenario validating second-line angiogenesis inhibition in colorectal cancer along with potential mechanism of resistance. We also critically described the available evidence recommending the use of the bevacizumab, aflibercept and ramucirumab in this setting with the final aim to guide the choice in the clinical practice.
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Affiliation(s)
- Riccardo Giampieri
- Medical Oncology Unit, Università Politecnica delle Marche, AOU "Ospedali Riuniti", Ancona, Italy
| | - Marta Caporale
- Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Filippo De Braud
- Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | | | - Valeria Pusceddu
- Medical Oncology,University Hospital, University of Cagliari, Cagliari, Italy
| | - Laura Demurtas
- Medical Oncology,University Hospital, University of Cagliari, Cagliari, Italy
| | - Angelo Restivo
- Colorectal Cancer Surgery, University Hospital, University of Cagliari, Cagliari, Italy
| | | | | | - Stefano Cascinu
- Medical Oncology Unit, Università Politecnica delle Marche, AOU "Ospedali Riuniti", Ancona, Italy
| | - Mario Scartozzi
- Medical Oncology,University Hospital, University of Cagliari, Cagliari, Italy.
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16
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Casey SC, Amedei A, Aquilano K, Azmi AS, Benencia F, Bhakta D, Bilsland AE, Boosani CS, Chen S, Ciriolo MR, Crawford S, Fujii H, Georgakilas AG, Guha G, Halicka D, Helferich WG, Heneberg P, Honoki K, Keith WN, Kerkar SP, Mohammed SI, Niccolai E, Nowsheen S, Vasantha Rupasinghe HP, Samadi A, Singh N, Talib WH, Venkateswaran V, Whelan RL, Yang X, Felsher DW. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol 2015; 35 Suppl:S199-S223. [PMID: 25865775 PMCID: PMC4930000 DOI: 10.1016/j.semcancer.2015.02.007] [Citation(s) in RCA: 264] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 02/26/2015] [Accepted: 02/27/2015] [Indexed: 02/06/2023]
Abstract
Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.
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Affiliation(s)
- Stephanie C Casey
- Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, United States
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Asfar S Azmi
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Fabian Benencia
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
| | - Dipita Bhakta
- School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, Tamil Nadu, India
| | - Alan E Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Chandra S Boosani
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
| | - Sophie Chen
- Ovarian and Prostate Cancer Research Laboratory, Guildford, Surrey, United Kingdom
| | | | - Sarah Crawford
- Department of Biology, Southern Connecticut State University, New Haven, CT, United States
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece
| | - Gunjan Guha
- School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, Tamil Nadu, India
| | | | - William G Helferich
- University of Illinois at Urbana-Champaign, Champaign-Urbana, IL, United States
| | - Petr Heneberg
- Charles University in Prague, Third Faculty of Medicine, Prague, Czech Republic
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Sid P Kerkar
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | | | - Somaira Nowsheen
- Medical Scientist Training Program, Mayo Graduate School, Mayo Medical School, Mayo Clinic, Rochester, MN, United States
| | - H P Vasantha Rupasinghe
- Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Nova Scotia, Canada
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Wamidh H Talib
- Department of Clinical Pharmacy and Therapeutics, Applied Science University, Amman, Jordan
| | | | - Richard L Whelan
- Mount Sinai Roosevelt Hospital, Icahn Mount Sinai School of Medicine, New York City, NY, United States
| | - Xujuan Yang
- University of Illinois at Urbana-Champaign, Champaign-Urbana, IL, United States
| | - Dean W Felsher
- Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, United States.
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17
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Moughon DL, He H, Schokrpur S, Jiang ZK, Yaqoob M, David J, Lin C, Iruela-Arispe ML, Dorigo O, Wu L. Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer. Cancer Res 2015; 75:4742-52. [PMID: 26471360 DOI: 10.1158/0008-5472.can-14-3373] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 08/23/2015] [Indexed: 11/16/2022]
Abstract
Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC.
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Affiliation(s)
- Diana L Moughon
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Huanhuan He
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, California
| | - Shiruyeh Schokrpur
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Ziyue Karen Jiang
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Madeeha Yaqoob
- Department of Surgery and Cancer, Hammersmith hospital, Imperial College London, London, United Kingdom
| | - John David
- Department of Molecular and Medical Pharmacology, California Nanosystems Institute, Los Angeles, California
| | - Crystal Lin
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - M Luisa Iruela-Arispe
- Department of Molecular, Cell and Developmental Biology, Los Angeles, California. Molecular Biology Institute, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California
| | - Oliver Dorigo
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, California
| | - Lily Wu
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
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18
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Kuhnert F, Chen G, Coetzee S, Thambi N, Hickey C, Shan J, Kovalenko P, Noguera-Troise I, Smith E, Fairhurst J, Andreev J, Kirshner JR, Papadopoulos N, Thurston G. Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer. Cancer Res 2015; 75:4086-96. [PMID: 26377940 DOI: 10.1158/0008-5472.can-14-3773] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 07/14/2015] [Indexed: 11/16/2022]
Abstract
The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade.
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Affiliation(s)
- Frank Kuhnert
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
| | - Guoying Chen
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | | | - Nithya Thambi
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Carlos Hickey
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Jing Shan
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | | | | | - Eric Smith
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
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19
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Abstract
Angiogenesis is the process through which new blood vessels are formed from pre-existing vessels and is essential for the growth of all solid tumors. Vascular endothelial growth factor (VEGF) is a regulator of angiogenesis, which is crucial for tumor growth and metastasis. Its inhibition with antiangiogenic drugs is thought to improve delivery of chemotherapy through vascular normalization and disruption of tumor vasculature. Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR)1 and VEGFR2 extracellular domains that binds to VEGF-A, VEGF-B, placental growth factor (PlGF) 1 and 2. Aflibercept has demonstrated preclinical efficacy in different tumor types and exerts its antiangiogenic effects through regression of tumor vasculature, remolding of vasculature, and inhibition of new tumor vessel growth. This review examines the effects of aflibercept on tumor vasculature and on different types of solid tumors, and explores the preclinical and clinical benefits of inclusion aflibercept into anticancer treatment strategies.
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Affiliation(s)
- Vincenzo Ricci
- Oncology Department, San Raffaele Institute, 60, Olgettina St., 20132 Milan, Italy
| | - Monica Ronzoni
- Oncology Department, San Raffaele Institute, 60, Olgettina St., 20132 Milan, Italy
| | - Teresa Fabozzi
- San Raffaele Institute, 60, Olgettina St., 20132 Milan, Italy
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20
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Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition. Cancer Metastasis Rev 2015; 33:17-39. [PMID: 24357056 DOI: 10.1007/s10555-013-9456-2] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ovarian adenocarcinoma is characterized by a late detection, dissemination of cancer cells into the whole peritoneum, and the frequent acquisition of chemoresistance. If these particularities can be explained in part by intrinsic properties of ovarian cancer cells, an increased number of studies show the importance of the tumor microenvironment in tumor progression. Ovarian cancer cells can regulate the composition of their stroma in promoting the formation of ascitic fluid, rich in cytokines and bioactive lipids, and in stimulating the differentiation of stromal cells into a pro-tumoral phenotype. In return, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, tumor-associated macrophages, or other peritoneal cells, such as adipocytes and mesothelial cells can regulate tumor growth, angiogenesis, dissemination, and chemoresistance. This review focuses on the current knowledge about the roles of stromal cells and the associated secreted factors on tumor progression. We also summarize the different studies showing that targeting the microenvironment represents a great potential for improving the prognosis of patients with ovarian adenocarcinoma.
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21
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Noorani L, Stenzel M, Liang R, Pourgholami MH, Morris DL. Albumin nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft model. J Nanobiotechnology 2015; 13:25. [PMID: 25890381 PMCID: PMC4409778 DOI: 10.1186/s12951-015-0082-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 03/02/2015] [Indexed: 12/31/2022] Open
Abstract
Background The poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments. Albendazole (ABZ) is an anti-parasite compound capable of impairing microtubule formation. We hypothesized that ABZ could be repurposed as a potential anti-angiogenic drug due to its potent inhibition of vascular endothelial growth factor (VEGF) in ovarian cancer with ascites. However, the poor aqueous solubility of ABZ limits its potential for cancer therapy. In this study, we have assembled ABZ with bovine serum albumin into nanoparticles with a size range of 7–10 nm (BSA-ABZ) and 200–250 nm (Nab-ABZ). We further examined the anticancer effects of ABZ carrying nanoparticles in ovarian cancer cells, in both in vitro and in vivo models. Results Drug release studies demonstrated that about 93% of ABZ was released from BSA-ABZ 10 nm in comparison to 83% from Nab-ABZ 200 nm at pH 7.4 in 8 days. In vitro cell proliferation studies showed that the BSA-ABZ 10 nm exhibited the highest killing efficacy of ovarian cancer cells with surprisingly least toxicity to healthy ovarian epithelial cells. Confocal microscopy and fluorescence activated cell sorting analysis (FACS) revealed more efficient internalization of the BSA-ABZ 10 nm by cancer cells. For in vivo studies, we examined the tumor growth, ascites formation and the expression of VEGF and secreted protein acidic and rich in cysteine (SPARC) in tumor samples and only VEGF in plasma samples. The BSA-ABZ 10 nm reduced the tumor burden significantly (p < 0.02) at a much lower drug dose (10 μg/ml) compare to free drug. Both formulations were capable of suppressing the ascites volume significantly (p < 0.05) and reducing the number of ascites cells. The expression of VEGF and SPARC was also reduced, which indicates the underlying therapeutic mechanism of the ABZ. Conclusion Our data suggest that the BSA-ABZ may hold promise for the treatment and control of progression of ovarian cancer with ascites. However further studies are required to examine the efficacy of both the formulations in aggressive models of recurrent ovarian cancer with respect to particle size and dosing parameters. Electronic supplementary material The online version of this article (doi:10.1186/s12951-015-0082-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lubna Noorani
- Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW, Australia. .,Department of Surgery, St. George Clinical School, Faculty of Medicine, University of New South Wales, Kogarah, NSW, Australia.
| | - Martina Stenzel
- Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
| | - Roger Liang
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
| | - Mohammad H Pourgholami
- Department of Surgery, St. George Clinical School, Faculty of Medicine, University of New South Wales, Kogarah, NSW, Australia.
| | - David L Morris
- Department of Surgery, St. George Clinical School, Faculty of Medicine, University of New South Wales, Kogarah, NSW, Australia.
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22
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Ohman AW, Hasan N, Dinulescu DM. Advances in tumor screening, imaging, and avatar technologies for high-grade serous ovarian cancer. Front Oncol 2014; 4:322. [PMID: 25478323 PMCID: PMC4235464 DOI: 10.3389/fonc.2014.00322] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 10/27/2014] [Indexed: 12/19/2022] Open
Abstract
The majority of high-grade serous ovarian carcinoma cases are detected in advanced stages when treatment options are limited. Surgery is less effective at eradicating the disease when it is widespread, resulting in high rates of disease relapse and chemoresistance. Current screening techniques are ineffective for early tumor detection and consequently, BRCA mutations carriers, with an increased risk for developing high-grade serous ovarian cancer, elect to undergo risk-reducing surgery. While prophylactic surgery is associated with a significant reduction in the risk of cancer development, it also results in surgical menopause and significant adverse side effects. The development of efficient early-stage screening protocols and imaging technologies is critical to improving the outcome and quality of life for current patients and women at increased risk. In addition, more accurate animal models are necessary in order to provide relevant in vivo testing systems and advance our understanding of the disease origin and progression. Moreover, both genetically engineered and tumor xenograft animal models enable the preclinical testing of novel imaging techniques and molecularly targeted therapies as they become available. Recent advances in xenograft technologies have made possible the creation of avatar mice, personalized tumorgrafts, which can be used as therapy testing surrogates for individual patients prior to or during treatment. High-grade serous ovarian cancer may be an ideal candidate for use with avatar models based on key characteristics of the tumorgraft platform. This review explores multiple strategies, including novel imaging and screening technologies in both patients and animal models, aimed at detecting cancer in the early-stages and improving the disease prognosis.
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Affiliation(s)
- Anders W Ohman
- Division of Women's and Perinatal Pathology, Department of Pathology, Eugene Braunwald Research Center, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA
| | - Noor Hasan
- Division of Women's and Perinatal Pathology, Department of Pathology, Eugene Braunwald Research Center, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA
| | - Daniela M Dinulescu
- Division of Women's and Perinatal Pathology, Department of Pathology, Eugene Braunwald Research Center, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA
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23
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Recurrent ascites in a patient with low-grade astrocytoma and ventriculo-peritoneal shunt treated with the multikinase inhibitor sorafenib. J Pediatr Hematol Oncol 2014; 36:e533-5. [PMID: 24351969 DOI: 10.1097/mph.0000000000000094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
This report describes a 6-year-old boy with disseminated low-grade astrocytoma and ventriculo-peritoneal shunt, who developed recurrent ascites while receiving sorafenib on a clinical trial. Laboratory analysis of the peritoneal fluid showed no elevation of protein content and no evidence of underlying infection or tumor dissemination. This report highlights ascites as a previously unrecognized adverse reaction to sorafenib in a patient with a ventriculo-peritoneal shunt. We conclude that such patients should be closely monitored for this complication when treated with sorafenib.
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24
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Abstract
Aflibercept (known as ziv-aflibercept in the USA and sold under the trade name Zaltrap®) is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factors A and B and placental growth factor. Its unique mechanism of action with respect to other agents targeting angiogenesis led investigators to speculate that it may be more ubiquitously efficacious in tumors highly dependent on pathologic angiogenesis for their growth. Despite encouraging preclinical studies in various tumor types, aflibercept has not been proven efficacious in most later-phase clinical studies. In fact, its only currently held US Food and Drug Administration indication is in metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin, and irinotecan for those patients previously treated with an oxaliplatin-containing chemotherapy regimen. Given aflibercept's toxicity profile and cost, further investigation is needed to better understand its mechanism of action and to discover predictive biomarkers for optimization of its appropriate use in treatment of cancer patients.
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Recondo GJ, Díaz-Cantón E, de la Vega M, Greco M, Recondo GS, Valsecchi ME. Advances and new perspectives in the treatment of metastatic colon cancer. World J Gastrointest Oncol 2014; 6:211-24. [PMID: 25024813 PMCID: PMC4092338 DOI: 10.4251/wjgo.v6.i7.211] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/04/2014] [Accepted: 05/29/2014] [Indexed: 02/05/2023] Open
Abstract
During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer. Anti-angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes. However, this progress has paradoxically leaded us into new challenges. In many cases the clinical development was done in parallel and the lack of head-to-head comparison evolved into circumstances where several valid new "standards of care" are available. Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision. In addition, progress never stops and new agents are continuously tested. For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature. Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease.
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Forsberg F, Ro RJ, Marshall A, Liu JB, Chiou SY, Merton DA, Machado P, Dicker AP, Nazarian LN. The Antiangiogenic Effects of a Vascular Endothelial Growth Factor Decoy Receptor Can Be Monitored in Vivo Using Contrast-Enhanced Ultrasound Imaging. Mol Imaging 2014. [DOI: 10.2310/7290.2013.00073] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Flemming Forsberg
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Raymond J. Ro
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Andrew Marshall
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Ji-Bin Liu
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - See-Ying Chiou
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Daniel A. Merton
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Priscilla Machado
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Adam P. Dicker
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
| | - Levon N. Nazarian
- From the Departments of Radiology and Radiation Oncology, Thomas Jefferson University, and School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA
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27
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Giordano G, Febbraro A, Venditti M, Campidoglio S, Olivieri N, Raieta K, Parcesepe P, Imbriani GC, Remo A, Pancione M. Targeting angiogenesis and tumor microenvironment in metastatic colorectal cancer: role of aflibercept. Gastroenterol Res Pract 2014; 2014:526178. [PMID: 25136356 PMCID: PMC4130202 DOI: 10.1155/2014/526178] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 04/12/2014] [Accepted: 04/27/2014] [Indexed: 02/08/2023] Open
Abstract
In the last decades, we have progressively observed an improvement in therapeutic options for metastatic colorectal cancer (mCRC) treatment with a progressive prolongation of survival. mCRC prognosis still remains poor with low percentage of 5-year survival. Targeted agents have improved results obtained with standard chemotherapy. Angiogenesis plays a crucial role in colorectal cancer growth, proliferation, and metastasization and it has been investigated as a potential target for mCRC treatment. Accordingly, novel antiangiogenic targeted agents bevacizumab, regorafenib, and aflibercept have been approved for mCRC treatment as the result of several phase III randomized trials. The development of a tumor permissive microenvironment via the aberrant expression by tumor cells of paracrine factors alters the tumor-stroma interactions inducing an expansion of proangiogenic signals. Recently, the VELOUR study showed that addition of aflibercept to FOLFIRI regimen as a second-line therapy for mCRC improved significantly OS, PFS, and RR. This molecule represents a valid second-line therapeutic option and its peculiar ability to interfere with placental growth factor (PlGF)/vascular endothelial growth factor receptor 1 (VEGFR1) axis makes it effective in targeting angiogenesis, inflammatory cells and in overcoming resistances to anti-angiogenic first-line treatment. Here, we discuss about Aflibercept peculiar ability to interfere with tumor microenvironment and angiogenic pathway.
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Affiliation(s)
- Guido Giordano
- 1Medical Oncology Unit, Ospedale Sacro Cuore di Gesù Fatebenefratelli, 82100 Benevento, Italy
- *Guido Giordano: and
| | - Antonio Febbraro
- 1Medical Oncology Unit, Ospedale Sacro Cuore di Gesù Fatebenefratelli, 82100 Benevento, Italy
| | - Michele Venditti
- 1Medical Oncology Unit, Ospedale Sacro Cuore di Gesù Fatebenefratelli, 82100 Benevento, Italy
| | - Serena Campidoglio
- 1Medical Oncology Unit, Ospedale Sacro Cuore di Gesù Fatebenefratelli, 82100 Benevento, Italy
| | - Nunzio Olivieri
- 2Department of Biology, Federico II University, 80131 Napoli, Italy
| | - Katia Raieta
- 3Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy
| | - Pietro Parcesepe
- 4Department of Surgical and Diagnostic Pathology, “G.B. Rossi” Hospital, University of Verona, 37134 Verona, Italy
| | - Giusy Carmen Imbriani
- 5Fifth Division of General Surgery and Special Surgical Techniques, Second University of Studies of Naples, 80138 Naples, Italy
| | - Andrea Remo
- 6Department of Pathology, “Mater Salutis” Hospital, 37045 Legnago, Italy
| | - Massimo Pancione
- 3Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy
- *Massimo Pancione:
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Efficacy and Safety of Aflibercept and Its Role in the Treatment of Metastatic Colorectal Cancer. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s40487-013-0002-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Lengyel E, Burdette JE, Kenny HA, Matei D, Pilrose J, Haluska P, Nephew KP, Hales DB, Stack MS. Epithelial ovarian cancer experimental models. Oncogene 2013; 33:3619-33. [PMID: 23934194 DOI: 10.1038/onc.2013.321] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 06/21/2013] [Accepted: 06/21/2013] [Indexed: 12/13/2022]
Abstract
Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge, and many approaches used to study other solid tumors (for example, lung, colon and breast) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment (TME). This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis and chemoresistance. As these new approaches more accurately recapitulate the complex TME, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge.
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Affiliation(s)
- E Lengyel
- Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | - J E Burdette
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois/Chicago, Chicago, IL, USA
| | - H A Kenny
- Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | - D Matei
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - J Pilrose
- Medical Sciences, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA
| | - P Haluska
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - K P Nephew
- Medical Sciences, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA
| | - D B Hales
- Department of Physiology, Southern Illinois University, Carbondale, IL, USA
| | - M S Stack
- Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA
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Hallaj-Nezhadi S, Dass CR, Lotfipour F. Intraperitoneal delivery of nanoparticles for cancer gene therapy. Future Oncol 2013; 9:59-68. [PMID: 23252564 DOI: 10.2217/fon.12.171] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Nanoparticle-based gene delivery systems may be more efficient for administration of therapeutic genes to solid tumors and cancer metastases, owing to the numerous advantages in terms of enhanced tissue penetrability, improved cellular uptake and targeted gene delivery to the cells of interest compared with other gene delivery systems. Intraperitoneal (IP) delivery of therapeutic agents offers special merits because of the anatomical situation of peritoneum for local cancer therapy. Via the IP administration route, it is possible to target the therapeutic agents exactly to the target cells and protect healthy tissues outside the peritoneal cavity from side effects. IP delivery could be applicable for the treatment of disorders of organs in the peritoneal cavity covered with peritoneum and subperitoneal connective tissue, including cancers such as ovarian and gastric. The goal of this article is to review the current state of IP delivery of nanoparticles for cancer gene therapy.
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Affiliation(s)
- Somayeh Hallaj-Nezhadi
- Pharmacy Faculty & Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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31
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Jitawatanarat P, Wee W. Update on antiangiogenic therapy in colorectal cancer: aflibercept and regorafenib. J Gastrointest Oncol 2013; 4:231-8. [PMID: 23730520 DOI: 10.3978/j.issn.2078-6891.2013.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Accepted: 02/22/2013] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis plays an important role in colorectal carcinogenesis and approaches targeting the vascular growth factor receptor (VEGF) signaling such as bevacizumab yielded significant survival improvement for metastatic colorectal cancer patients. Recent evidence demonstrated the benefit of continuing angiogenic suppression after first-progression following bevacizumab-containing cytotoxic regimen though no benefit was observed with the use of bevacizumab in adjuvant setting. Aflibercept, a soluble fusion protein with high affinity for VEGF-A, -B and PlGF, administered in combination with irinotecan-containing regimen improved the survival of metastatic colorectal cancer patients in second-line setting (VELOUR trial). Regorafenib, a small molecule multikinase inhibitor against various pro-angiogenic and -proliferation targets, improved the survival of metastatic colorectal cancer patients who had progressed on all standard therapy. These developments had renewed enthusiasm in the field and the role of aflibercept and regorafenib in other treatment settings will continue to be defined by on-going and future clinical trials. As other anti-angiogenic approaches are being tested clinically, other novel non-angiogenic targets deserve to be evaluated in our effort to improve the outcome of colorectal cancer patients.
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Harding V, Fenu E, Medani H, Shaboodien R, Ngan S, Li HK, Burt R, Diamantis N, Tuthill M, Blagden S, Gabra H, Urch CE, Moser S, Agarwal R. Safety, cost-effectiveness and feasibility of daycase paracentesis in the management of malignant ascites with a focus on ovarian cancer. Br J Cancer 2012; 107:925-30. [PMID: 22878372 PMCID: PMC3464770 DOI: 10.1038/bjc.2012.343] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 06/24/2012] [Accepted: 06/26/2012] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Paracentesis for malignant ascites is usually performed as an in-patient procedure, with a median length of stay (LoS) of 3-5 days, with intermittent clamping of the drain due to a perceived risk of hypotension. In this study, we assessed the safety of free drainage and the feasibility and cost-effectiveness of daycase paracentesis. METHOD Ovarian cancer admissions at Hammersmith Hospital between July and October 2009 were audited (Stage 1). A total of 21 patients (Stage 2) subsequently underwent paracentesis with free drainage of ascites without intermittent clamping (October 2010-January 2011). Finally, 13 patients (19 paracenteses, Stage 3), were drained as a daycase (May-December 2011). RESULTS Of 67 patients (Stage 1), 22% of admissions and 18% of bed-days were for paracentesis, with a median LoS of 4 days. In all, 81% of patients (Stage 2) drained completely without hypotension. Of four patients with hypotension, none was tachycardic or symptomatic. Daycase paracentesis achieved complete ascites drainage without complications, or the need for in-patient admission in 94.7% of cases (Stage 3), and cost £954 compared with £1473 for in-patient drainage. CONCLUSIONS Free drainage of malignant ascites is safe. Daycase paracentesis is feasible, cost-effective and reduces hospital admissions, and potentially represents the standard of care for patients with malignant ascites.
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Affiliation(s)
- V Harding
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - E Fenu
- National Clinical Guideline Centre, Royal College of Physicians, London NW1 4L, UK
| | - H Medani
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - R Shaboodien
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - S Ngan
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - H K Li
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - R Burt
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - N Diamantis
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - M Tuthill
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - S Blagden
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - H Gabra
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - C E Urch
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - S Moser
- Department of Radiology, Hammersmith Hospital, Imperial College, Du Cane Road, London W12 0HS, UK
| | - R Agarwal
- Department of Oncology, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
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33
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Eskander RN, Tewari KS. Emerging treatment options for management of malignant ascites in patients with ovarian cancer. Int J Womens Health 2012; 4:395-404. [PMID: 22927770 PMCID: PMC3422105 DOI: 10.2147/ijwh.s29467] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Malignant ascites affects approximately 10% of patients with recurrent epithelial ovarian cancer and is associated with troublesome symptoms, including abdominal pressure and distension, dyspnea, bloating, pelvic pain, and bowel/bladder dysfunction. To date, no effective therapy has been identified for the treatment of malignant ascites in patients with recurrent, advanced ovarian cancer. In this article, we discuss currently existing options for the treatment of ascites associated with ovarian cancer, and review the literature as it pertains to novel, targeted therapies. Specifically, preclinical and clinical trials exploring the use of the antiangiogenic agents, bevacizumab and vascular endothelial growth factor-trap, as well as the nonangiogenic agent, catumaxomab, will be reviewed. Despite current limitations in treatment, knowledge regarding management options in the palliation of ascites is critical to practicing physicians. Ultimately, as with all novel therapies, symptom relief and treatment goals must be weighed against patient discomfort and potentially significant adverse events.
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Affiliation(s)
- Ramez N Eskander
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California at Irvine, Irvine, CA, USA
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34
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Gaya A, Tse V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat Rev 2012; 38:484-93. [DOI: 10.1016/j.ctrv.2011.12.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 12/18/2011] [Indexed: 12/27/2022]
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35
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Masoumi Moghaddam S, Amini A, Morris DL, Pourgholami MH. Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. Cancer Metastasis Rev 2012; 31:143-62. [PMID: 22101807 PMCID: PMC3350632 DOI: 10.1007/s10555-011-9337-5] [Citation(s) in RCA: 151] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination.
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Affiliation(s)
- Samar Masoumi Moghaddam
- Cancer Research Laboratories, Department of Surgery, St George Hospital, University of New South Wales, Sydney, NSW 2217 Australia
| | - Afshin Amini
- Cancer Research Laboratories, Department of Surgery, St George Hospital, University of New South Wales, Sydney, NSW 2217 Australia
| | - David L. Morris
- Department of Surgery, St George Hospital, University of New South Wales, Sydney, NSW 2217 Australia
| | - Mohammad H. Pourgholami
- Cancer Research Laboratories, Department of Surgery, St George Hospital, University of New South Wales, Sydney, NSW 2217 Australia
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36
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van der Bilt ARM, de Vries EGE, de Jong S, Timmer-Bosscha H, van der Zee AGJ, Reyners AKL. Turning promise into progress for antiangiogenic agents in epithelial ovarian cancer. Crit Rev Oncol Hematol 2012; 84:224-42. [PMID: 22525643 DOI: 10.1016/j.critrevonc.2012.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 03/13/2012] [Accepted: 03/16/2012] [Indexed: 12/16/2022] Open
Abstract
Despite efforts to improve chemotherapeutic efficacy in epithelial ovarian cancer, outcome for patients with advanced disease has remained unchanged since the introduction of standard carboplatin and paclitaxel. Interest has therefore shifted toward molecularly targeted therapies that interfere with important features of ovarian carcinogenesis, such as angiogenesis. Several angiogenesis inhibitors, targeting vascular endothelial growth factor (VEGF) ligands (bevacizumab, VEGF-Trap) or their receptors (VEGFR-targeted tyrosine kinase inhibitors) have been clinically evaluated. These agents demonstrated efficacy in phase II clinical trials. Results from phase III trials, in which bevacizumab was added to standard frontline chemotherapy, show a modest effect. Although the initial expectations for angiogenesis inhibitors have been tempered, further research is warranted to define their precise place in the treatment of ovarian cancer. This review summarizes the performed and ongoing studies with regard to angiogenesis inhibitors in ovarian cancer, and the available data on biomarkers for response prediction. Preclinical studies evaluating alternative angiogenesis inhibitors will also be discussed.
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Affiliation(s)
- Arne R M van der Bilt
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands
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37
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He K, Cui B, Li G, Wang H, Jin K, Teng L. The effect of anti-VEGF drugs (bevacizumab and aflibercept) on the survival of patients with metastatic colorectal cancer (mCRC). Onco Targets Ther 2012; 5:59-65. [PMID: 22570554 PMCID: PMC3345882 DOI: 10.2147/ott.s29719] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.
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Affiliation(s)
- Kuifeng He
- Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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38
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A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol 2012; 125:42-7. [DOI: 10.1016/j.ygyno.2011.11.021] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 11/08/2011] [Accepted: 11/12/2011] [Indexed: 02/06/2023]
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39
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Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma. Int J Cancer 2012; 131:2394-401. [DOI: 10.1002/ijc.27495] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Accepted: 02/02/2012] [Indexed: 02/03/2023]
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40
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Gotlieb WH, Amant F, Advani S, Goswami C, Hirte H, Provencher D, Somani N, Yamada SD, Tamby JF, Vergote I. Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 2012; 13:154-62. [DOI: 10.1016/s1470-2045(11)70338-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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41
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A phase I study of subcutaneously administered aflibercept (VEGF trap) in a new formulation in patients with advanced solid tumors. Invest New Drugs 2011; 30:1958-61. [PMID: 22002018 PMCID: PMC3432791 DOI: 10.1007/s10637-011-9753-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Accepted: 09/29/2011] [Indexed: 12/27/2022]
Abstract
Targeting angiogenesis is a valid anti-cancer strategy. Aflibercept is designed to sequester circulating vascular endothelial growth factor (VEGF) by preventing VEGF from binding to its receptors. This phase I study was to evaluate a new formulation of subcutaneously administered aflibercept in patients with advanced solid tumors. Here we report our experience with the toxicity, pharmacokinetic profile and efficacy of the new 100 mg/mL subcutaneous (SC) formulation of aflibercept administered at a dose of at 4 mg/kg every 2 weeks.
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42
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Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Lancet Oncol 2011; 12:1109-17. [PMID: 21992853 DOI: 10.1016/s1470-2045(11)70244-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. METHODS For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501. FINDINGS From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%). INTERPRETATION Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted. FUNDING US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.
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Amini A, Masoumi Moghaddam S, Morris DL, Pourgholami MH. Utility of vascular endothelial growth factor inhibitors in the treatment of ovarian cancer: from concept to application. JOURNAL OF ONCOLOGY 2011; 2012:540791. [PMID: 21961001 PMCID: PMC3180777 DOI: 10.1155/2012/540791] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 05/26/2011] [Accepted: 05/26/2011] [Indexed: 12/20/2022]
Abstract
Despite recent advances in the management of ovarian cancer, it remains the most lethal gynecologic malignancy. Vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in the progression of ovarian cancer leading to the eventual development of malignant ascites. On this basis, agents rendering VEGF ineffective by neutralizing VEGF (bevacizumab), blocking its receptors (aflibercept), or interfering with the postreceptor signaling pathways (sunitinib) provide us with the rational treatment options. These agents are generally used in combination with the standard chemotherapeutic drugs. Here, we discuss the basis of and the logic behind the use of these agents in the treatment of epithelial ovarian cancer, as well as their evaluation in different preclinical and clinical studies.
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Affiliation(s)
- Afshin Amini
- Cancer Research Laboratories, Department of Surgery, St George Hospital (SESIAHS), The University of New South Wales, Sydney, NSW 2217, Australia
| | - Samar Masoumi Moghaddam
- Cancer Research Laboratories, Department of Surgery, St George Hospital (SESIAHS), The University of New South Wales, Sydney, NSW 2217, Australia
| | - David L. Morris
- Department of Surgery, St George Hospital (SESIAHS), The University of New South Wales, Sydney, NSW 2217, Australia
| | - Mohammad H. Pourgholami
- Cancer Research Laboratories, Department of Surgery, St George Hospital (SESIAHS), The University of New South Wales, Sydney, NSW 2217, Australia
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Sullivan LA, Brekken RA. The VEGF family in cancer and antibody-based strategies for their inhibition. MAbs 2011; 2:165-75. [PMID: 20190566 DOI: 10.4161/mabs.2.2.11360] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis is required in normal physiological processes, but is also involved in tumor growth, progression and metastasis. Vascular endothelial growth factor (VEGF), a primary mediator of angiogenesis in normal physiology and in disease, and other VEGF family members and their receptors provide targets that have been explored extensively for cancer therapy. Small molecule inhibitors and antibody/protein-based strategies that target the VEGF pathway have been studied in multiple types of cancer. This review will focus on VEGF pathway targeting antibodies that are currently being evaluated in pre-clinical and clinical studies.
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Affiliation(s)
- Laura A Sullivan
- Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, USA
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Abstract
All human cells, including cancer cells, need oxygen and nutrients to survive. A widely used strategy to combat cancer is therefore the starvation of tumor cells by cutting off the blood supply of tumors. Clinical experience indeed shows that tumor progression can be delayed by anti-angiogenic agents. However, emerging evidence indicates that in certain experimental conditions, hypoxia as a result of pruning of the tumor microvasculature can promote tumor invasion and metastasis, although these findings are contextual and debated. Genetic studies in mice unveiled that vascular-targeting strategies that avoid aggravation of tumor hypoxia or even promote tumor oxygenation might prevent such an invasive metastatic switch. In this article, we will discuss the emerging link between hypoxia signaling and the various steps of metastasis.
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Wertel I, Nowicka A, Rogala E, Kotarski J. Peritoneal Immune System in Patients with Advance Epithelial Ovarian Cancer. Int Rev Immunol 2011; 30:87-101. [DOI: 10.3109/08830185.2011.569902] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 122:111-5. [PMID: 21497382 DOI: 10.1016/j.ygyno.2011.03.036] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 03/25/2011] [Accepted: 03/30/2011] [Indexed: 11/22/2022]
Abstract
BACKGROUND Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel. METHODS Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n = 5) or recurrence within 6 months of treatment completion (n = 42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m² days 1, 8, and 15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%). RESULTS Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34-78) years, serous histology: 72%, and high-grade: 81%. EFFICACY one complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95% CI: 2.2-6.7); overall survival was 17.4 months (95% CI: 13.2-20.8). Seventeen patients (36%) had PFS > 6 months. TOXICITY there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1. CONCLUSIONS Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.
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Choi EK, Kim SW, Nam EJ, Paek J, Yim GW, Kang MH, Kim YT. Differential effect of intraperitoneal albendazole and paclitaxel on ascites formation and expression of vascular endothelial growth factor in ovarian cancer cell-bearing athymic nude mice. Reprod Sci 2011; 18:763-71. [PMID: 21421899 DOI: 10.1177/1933719111398142] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES The purposes of our study were to evaluate the effect of intraperitoneal albendazole on tumor growth, ascites formation, and vascular endothelial growth factor (VEGF) mRNA expression, and to assess the synergistic effect of paclitaxel in OVCAR-3-bearing nude mice. METHODS In all, 4 groups of mice were injected intraperitoneally with weekly albendazole (450 mg/kg per week), paclitaxel (30 mg/kg per week), albendazole plus paclitaxel, or normal saline for 4 weeks. RESULTS Ascitic fluid accumulation (2.47, 2.65, 2.88, and 5.90 mL, respectively) and in ascitic VEGF levels were significantly reduced in the 3 treatment groups compared to the control group (170.83, 229.16, 267, and 1625 pg/mL, respectively). However, complete tumor suppression was more prominent in the paclitaxel group, and VEGF mRNA expression was more strongly inhibited in the albendazole group (P < .05). No synergistic effect of albendazole and paclitaxel was observed. CONCLUSION We demonstrated a differential effect of albendazole and paclitaxel in a xenograft model of ovarian carcinoma; albendazole suppressed ascites formation by inhibiting VEGF secretion, and paclitaxel exerted its effects by direct cytotoxicity.
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Affiliation(s)
- Eun-Kyoung Choi
- The Department of Obstetrics and Gynecology, NHIC Ilsan Hospital, Koyang, South Korea
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Liao S, Liu J, Lin P, Shi T, Jain RK, Xu L. TGF-beta blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models. Clin Cancer Res 2011; 17:1415-24. [PMID: 21278244 DOI: 10.1158/1078-0432.ccr-10-2429] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Ovarian cancer patients with malignant ascites have poor prognosis. The accumulation of ascites is caused by an imbalance between fluid extravasation from the blood vessels and reabsorption by lymphatic vessels. Whereas, the role of TGF-β in tumor progression has been well studied, the role of TGF-β in lymphatic vessel function is far from understood. Here, we sought to dissect the role of TGF-β blockade in the formation of ascites. EXPERIMENTAL DESIGN We used soluble TGF-β Receptor II (sTβRII) to block TGF-β signaling in two orthotopic human ovarian carcinoma models: SKOV3ip1 and Hey-A8. We measured tumor proliferation, apoptosis, lymphangiogenesis, and angiogenesis by immunohistochemical staining, and examined diaphragm lymphatic vessel network by intraperitoneal injection of a fluorescent dye. Diaphragm lymphatic vessel function was assessed by tracking fluorescent beads in the diaphragm and measuring their drainage rate. RESULTS TGF-β blockade impaired tumor growth in both models, accompanied by a decreased tumor cell proliferation and angiogenesis. More strikingly, TGF-β blockade almost completely abolished ascites formation. TGF-β blockade significantly inhibited the expression of VEGF, which is the major contributor to ascites formation. At the same time, TGF-β blockade prevent 'abnormalization' of diaphragm lymphatic vessels and improved ascites drainage. CONCLUSIONS TGF-β blockade decreased ascites by both inhibiting ascites formation and improving ascites drainage. Based on our finding, it is reasonable to consider the use of TGF-β blockade as a palliative treatment for symptomatic ascites.
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Affiliation(s)
- Shan Liao
- Edwin L Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Gavalas NG, Karadimou A, Dimopoulos MA, Bamias A. Immune response in ovarian cancer: how is the immune system involved in prognosis and therapy: potential for treatment utilization. Clin Dev Immunol 2011; 2010:791603. [PMID: 21318181 PMCID: PMC3034919 DOI: 10.1155/2010/791603] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 12/17/2010] [Indexed: 12/03/2022]
Abstract
Ovarian cancer is one of the leading causes of cancer-related death among women. Resistance to the disease occurs in more than 70% of the cases even after treated with chemotherapy agents such as paclitaxel- and platinum-based agents. The immune system is increasingly becoming a target for intense research in order to study the host's immune response against ovarian cancer. T cell populations, including NK T cells and Tregs, and cytokines have been associated with disease outcome, indicating their increasing clinical significance, having been associated with prognosis and as markers of disease progress, respectively. Harnessing the immune system capacity in order to induce antitumor response remains a major challenge. This paper examines the recent developments in our understanding of the mechanisms of development of the immune response in ovarian cancer as well as its prognostic significance and the existing experience in clinical studies.
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Affiliation(s)
- Nikos G. Gavalas
- Department of Clinical Therapeutics, Medical School, University of Athens, Alexandra Hospital, 80 Vasilissis Sofias Avenue, 115 28 Athens, Greece
| | - Alexandra Karadimou
- Department of Clinical Therapeutics, Medical School, University of Athens, Alexandra Hospital, 80 Vasilissis Sofias Avenue, 115 28 Athens, Greece
| | - Meletios A. Dimopoulos
- Department of Clinical Therapeutics, Medical School, University of Athens, Alexandra Hospital, 80 Vasilissis Sofias Avenue, 115 28 Athens, Greece
| | - Aristotelis Bamias
- Department of Clinical Therapeutics, Medical School, University of Athens, Alexandra Hospital, 80 Vasilissis Sofias Avenue, 115 28 Athens, Greece
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