Molecularly targeted drugs for metastatic colorectal cancer

Cheng, Ying-dong; Yang, Hua; Zhang, Zhi-cao

doi:10.2147/dddt.s52485

Cited by 22 publications

(14 citation statements)

References 81 publications

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“…5G-5L, Supplementary Table ST7, Supplementary Fig. S4G-S4J) consistent with known sensitivity of KRAS WT colon cancer to inhibition of EGFR and approval of cetuximab (35). …”

Section: Resultssupporting

confidence: 75%

Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

et al. 2017

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Precision Medicine is an approach that takes into account the influence of individuals' genes, environment and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform, which integrates whole exome sequencing (WES) with a living biobank that enables high throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures, and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an IRB approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high throughput drug screening effective strategies. Analysis of tumor derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted.

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“…5G-5L, Supplementary Table ST7, Supplementary Fig. S4G-S4J) consistent with known sensitivity of KRAS WT colon cancer to inhibition of EGFR and approval of cetuximab (35). …”

Section: Resultssupporting

confidence: 75%

Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

et al. 2017

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“…Progression-free and overall survival in patients with mCRC was improved greatly by the addition of anti-VEGF and/or anti-EGFR to standard chemotherapy, in either first- or second-line treatment. [ 12 , 55 ]. However, several clinical results have suggested that VEGF and EGFR combinatory therapy do not improve the overall prognosis in CRC [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Angiogenesis, the process leading to the formation of new blood vessels, plays an important role in tumor development and distant metastasis [ 8 ], and its induction is mediated by numerous angiogenic factors [ 9 ]. Among these factors, vascular endothelial growth factor (VEGF) and its receptors are the most potent molecules activating endothelial cells metastasis and increasing vascular permeability [ 10 – 12 ]. Inhibition of VEGF activity has been reported to suppress the proliferation of cancer cells and improve the prognosis for unresectable CRC patients [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, epidermal growth factor receptor (EGFR), which plays an important role in tumorigenesis, is overexpressed in many types of cancers, especially in CRC [ 14 , 15 ]. According to the European and US guidelines, EGFR targeting-therapy has been recommended for the treatment of metastatic colorectal cancer (mCRC) [ 12 ]. However, not all patients have a good response to anti-EGFR treatment, and there is important clinical value for identifying predictors of treatment benefit or lack thereof [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Combined application of anti-VEGF and anti-EGFR attenuates the growth and angiogenesis of colorectal cancer mainly through suppressing AKT and ERK signaling in mice model

Ding

Yang

et al. 2016

BMC Cancer

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BackgroundAngiogenesis is generally involved during the cancer development and hematogenous metastasis. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are considered to have an important role in tumor-associated angiogenesis. However, the effects of simultaneously targeting on VEGF and EGFR on the growth and angiogenesis of colorectal cancer (CRC), and its underlying mechanisms remain unknown.MethodsImmunohistochemical staining was used to detect the VEGF and EGFR expression in different CRC tissue specimens, and the correlation between VEGF/EGFR expression with the clinicopathologic features was analyzed. Cell counting kit‑8 (CCK-8) and transwell assays were used to assess the cellular proliferation and invasion of CRC cells after treated with anti-VEGF antibody and/or anti-EGFR antibody in vitro, respectively. Moreover, in vivo tumor formation was performed on nude mice model, and the tumor microvessel density (MVD) was determined by anti-CD34 staining in different groups. Finally, we evaluated the impact of anti-VEGF antibody and/or anti-EGFR antibody on the activation of downstream signaling effectors using western blot.ResultsVEGF and EGFR were upregulated in CRC tissues, and their expression levels were correlated with hepatic metastasis. Blockage on VEGF or EGFR alone could inhibit the cellular proliferation and metastasis while their combination could reach a good synergism in vitro. In addition, in vivo xenograft mice model demonstrated that the tumor formation and angiogenesis were strongly suppressed by combination treatment of anti-VEGF and anti-EGFR antibodies. Besides, the combination treatment significantly reduced the activation of AKT and ERK1/2, but barely affected the activation of c-Myc, NF-κB/p65 and IκBα in CRC cells tumors. Interestingly, anti-VEGF antibody or anti-EGFR antibody alone could attenuate the phosphorylation of STAT3 as compared with negative control group, whereas the combined application not further suppressed but at least partially restored the activation of STAT3 in vivo.ConclusionsSimultaneous targeting on VEGF and EGFR does show significant inhibition on CRC tumor growth and angiogenesis in mice model, and these effects are mainly attributed to suppression of the AKT and ERK signaling pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2834-8) contains supplementary material, which is available to authorized users.

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“…While aflibercept is available in a single-use glass vial designed to provide 0.05 ml of 40 mg/ml solution (2 mg) for intravitreal injection, ziv-aflibercept is available as 100 mg per 4 ml (25 mg per ml) solution or 200 mg per 8 ml (25 mg per ml) solution, in a single-use vial. Aflibercept is iso-osmolar, whereas ziv-aflibercept is hyperosmolar (1000 mOsm/l) relative to the vitreous [15, 16]. …”

Section: Fusion Proteins: History Chemistry Production and Biologymentioning

confidence: 99%

Fusion proteins for treatment of retinal diseases: aflibercept, ziv-aflibercept, and conbercept

et al. 2016

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In the last few years, monoclonal antibodies have revolutionized the treatment of retinal neovascular diseases. More recently, a different class of drugs, fusion proteins, has provided an alternative treatment strategy with pharmacological differences. In addition to commercially available aflibercept, two other drugs, ziv-aflibercept and conbercept, have been studied in antiangiogenic treatment of ocular diseases. In this scenario, a critical review of the currently available data regarding fusion proteins in ophthalmic diseases may be a timely and important contribution. Aflibercept, previously known as VEGF Trap Eye, is a fusion protein of VEGF receptors 1 and 2 and a treatment for several retinal diseases related to angiogenesis. It has firmly joined ranibizumab and bevacizumab as an important therapeutic option in the management of neovascular AMD-, DME- and RVO-associated macular edema. Ziv-aflibercept, a systemic chemotherapeutic agent approved for the treatment of metastatic colorectal cancer, has recently drawn attention because of its potential for intravitreal administration, since it was not associated with ERG-related signs of toxicity in an experimental study and in human case reports. Conbercept is a soluble receptor decoy that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and PlGF, which has a high binding affinity for VEGF and a long half-life in vitreous. It has been studied in a phase three clinical trial and has shown efficacy and safety. This review discusses three fusion proteins that have been studied in ophthalmology, aflibercept, ziv-aflibercept and conbercept, with emphasis on their clinical application for the treatment of retinal diseases.

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Molecularly targeted drugs for metastatic colorectal cancer

Cited by 22 publications

References 81 publications

Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Combined application of anti-VEGF and anti-EGFR attenuates the growth and angiogenesis of colorectal cancer mainly through suppressing AKT and ERK signaling in mice model

Fusion proteins for treatment of retinal diseases: aflibercept, ziv-aflibercept, and conbercept

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