VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: The ALICE‐1 study

Scartozzi, Mario; Faloppi, Luca; Svegliati‐Baroni, Gianluca; Loretelli, Cristian; Piscaglia, Fabio; Iavarone, M.; Toniutto, Pierluigi; Fava, Giammarco; Minicis, S. De; Mandolesi, Alessandra; Bianconi, Maristella; Giampieri, Riccardo; Granito, Alessandro; Facchetti, F.; Bitetto, Davide; Marinelli, Sara; Venerandi, Laura; Vavassori, S.; Gemini, S; D’Errico, Antonietta; Colombo, Massimo; Bolondi, Luigi; Bearzi, Italo; Benedetti, Antonio; Cascinu, Stefano

doi:10.1002/ijc.28772

Cited by 122 publications

(90 citation statements)

References 39 publications

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“…On the other hand different studies investigated the impact of VEGF-A rs2010963 on clinical outcome during anti-angiogenesis therapy. According to present results, in advanced HCC receiving sorafenib patients harbouring the VEGF-A rs2010963 CC genotype showed a significantly improved overall and progression free survival 9 . Whether VEGF-A rs2010963 in our analysis may represent a prognostic or predictive factor is matter of debate.…”

Section: Discussionsupporting

confidence: 54%

“…The inhibition of tumour angiogenesis, primarily based on the vascular endothelial growth factor (VEGF)-driven pathway, is one of the primary mechanisms of action of regorafenib treatment. A growing body Scientific RepoRts | 6:25195 | DOI: 10.1038/srep25195 of evidence suggested a possible correlation between an altered expression of the angiogenetic pathway identified through polymorphisms analysis and global outcome in colorectal, gastric, breast, ovarian, renal cell and hepatocellular patients treated with drugs directed against tumour neoangiogenesis 8,9 . Remarkably all known VEGF polymorphisms are not located in the coding region, therefore different biological mechanisms in influencing gene expression and then clinical outcome have been proposed 10,11 .…”

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confidence: 99%

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Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.

Salvatore¹,

Prete²,

Prochilo³

et al. 2015

JCO

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Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs) with patients' progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.

Salvatore¹,

Prete²,

Prochilo³

et al. 2015

JCO

Self Cite

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“…VEGF stimulates endothelial-cell proliferation and induces budding in neovascularization (15). FGF-2 binds to heparin sulfate proteoglycans initially, and then the complex binds to the FGF receptor, leading to proliferation and angiogenesis (16,17).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma

Zhang

Tang

Zang

et al. 2017

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Abstract. Aim: The aim of the present study was to investigate the efficacy of the traditional Chinese medicine (TCM), astragaloside IV (AS-IV) and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma (HCC (FGF2), matrix metalloproteinase 2 (MMP2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), thrombosis-related factor tissue factor (TF) and coagulation factor VII (FVII), as well as microRNAs miR-122 and miR-221. Results: AS-IV and curcumin alone and in combination significantly reduced mean tumor weight compared to vehicle control (p<0.05). Tumor microvessel count was reduced by AS-IV and curcumin alone. Expression of FGF2, MMP2, VEGF, HGF, TF and FVII was reduced by AS-IV and curcumin alone. AS-IV and curcumin alone up-regulated expression of miR-122 and down-regulated that of miR-221. The combination of AS-IV and curcumin demonstrated significant synergistic effects on microvessel count as well as on expression of angiogenic and thrombosis-related factors and microRNAs. Conclusion: The present study indicates future clinical potential of combination therapy with AS-IV and curcumin for HCC.Hepatocellular carcinoma (HCC) is a highly aggressive and hypervascular tumor, associated with high morbidity (1), and is recalcitrant to therapy (2). Targeting angiogenesis could be an effective therapeutic strategy for controlling the progression of HCC.Traditional Chinese Medicine (TCM) has been widely used for anticancer treatment in China with a long history. Astragaloside IV (AS-IV) is a representative constituent of Astragalus membranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao and has various pharmacological activities, including anti-tumor, anti-inflammatory and anti-diabetic (3, 4). Curcumin (diferuloylmethane) is the chief component of the spice turmeric and is derived from the rhizome of the East Indian plant Curcuma longa. Curcumin exhibits anti inflammatory, antioxidant and anticancer efficacy (5). AS-IV was reported to reduce invasiveness and angiogenesis of gastric cancer cells and down-regulate the expression of fibroblast growth factor-2 (FGF-2) and suppress angiogenesis of HCT-116 colon cancer cells (6, 7). Curcumin showed anti-metastatic and anti-angiogenesis efficacy against small-cell lung cancer 465

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“…In contrast to other epithelial cancers such as breast, ovarian and colon, no mutations of common oncogenes and tumor suppressor genes except TP53 have been identified in HCC cells. However, many growth factor receptors such as epidermal growth factor receptor (EGFR), plateletderived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR) as well as key oncogenic signaling pathways related to proliferation and angiogenesis such as Ras/Raf/MEK/ERK (MAPK), phoshoinositol-3 kinase (PI3k)/Akt/mTOR, hepatocyte growth factor (HGF)/c-mesenchymal epithelial transition factor (c-Met), insulin growth factor receptor(IGF), transforming growth factor-β (TGF-β), Wnt/β-catenin, Hedgehog and Notch have been shown to be involved in hepatocarcinogenesis [2,3]. Therefore, the tyrosine kinase inhibitor sorafenib has been used to block both tumor cell proliferation and angiogenesis by targeting Raf-1/B-Raf kinases and VEGFR-2/-3 and PDGFR-β tyrosine kinases.…”

Section: Pi3k/akt Pathway Is Involved In the Sorafenib Resistancementioning

confidence: 99%

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance. Vaccination and improved treatment for hepatitis are the most effective means to reduce the burden of liver cancer worldwide. Expression of biomarkers such as AFP (alpha-fetoprotein), DDK1 (Dickkopf WNT Signaling Pathway Inhibitor 1) and microRNAs in blood are being tested for early screening of liver cancer. Since 2008, sorafenib has been used as the standard molecular targeting agent for HCC. However, overall outcomes for sorafenib alone or in combination with other tyrosine kinase inhibitors are unsatisfactory. Whether simultaneously or sequentially, addiction switches and compensatory pathway activation in HCC, induced by sorafenib treatment, may induce acquired resistance. Forkhead box M1 (FOXM1) and metadherin (MTDH) have been shown to be master regulators of different aspects of tumorigenesis, including angiogenesis, invasion, metastasis and drug resistance. Elevated expression of both FOXM1 and MTDH is known to be a consequence of both activating mutations in oncogenes such as PI3K, Ras, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN in various types of cancers including HCC. The role of FOXM1 and MTDH as potential prognostic markers as well as therapeutic targets in HCC will be discussed. In addition, microRNAs (miRNAs), endogenous small noncoding RNAs involved in the regulation of gene expression, are involved in HCC and interact with both FOXM1 and MTDH in several ways. Thus, altered expression of miRNAs in HCCs will also be discussed as potential tools for diagnosis, prognosis and therapy in HCC. OPEN ACCESS

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VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: The ALICE‐1 study

Cited by 122 publications

References 39 publications

Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.

Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.

Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

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