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Clinical utility of ramucirumab in advanced gastric cancer.

Chan MM, Sjoquist KM, Zalcberg JR - Biologics (2015)

Bottom Line: Prognosis remains poor with most patients presenting with advanced or metastatic disease.A better understanding of angiogenesis has led to the investigation of drugs that inhibit the vascular endothelial growth factor (VEGF) pathway including anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, sorafenib, apatinib, regorafenib), and inhibitors of vascular endothelial growth factor receptors (VEGFRs) (eg, ramucirumab).Ramucirumab, a VEGFR-2 inhibitor, is the first anti-angiogenic agent approved by the US Food and Drug Administration for use in the treatment of advanced gastric cancers.

View Article: PubMed Central - PubMed

Affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia ; Department of Medical Oncology, Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, Australia.

ABSTRACT
Gastric cancer is currently the third most common cause of cancer deaths worldwide. Prognosis remains poor with most patients presenting with advanced or metastatic disease. A better understanding of angiogenesis has led to the investigation of drugs that inhibit the vascular endothelial growth factor (VEGF) pathway including anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, sorafenib, apatinib, regorafenib), and inhibitors of vascular endothelial growth factor receptors (VEGFRs) (eg, ramucirumab). Ramucirumab, a VEGFR-2 inhibitor, is the first anti-angiogenic agent approved by the US Food and Drug Administration for use in the treatment of advanced gastric cancers. This review will focus on the clinical utility and potential use of ramucirumab in advanced gastric cancer.

No MeSH data available.


Related in: MedlinePlus

Strategies to inhibit VEGF pathway signaling.Notes: (A) anti-VEGF antibody (eg, bevacizumab); (B) anti-VEGFR-2 antibody (eg, ramucirumab); (C) soluble VEGF receptors (eg, aflibercept); and (D) VEGF receptor tyrosine kinase inhibitors (eg, sunitinib, sorafenib, regorafenib, apatinib [anti-VEGFR-2 TKI]).Abbreviations: Ab, antibody; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
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f1-btt-9-093: Strategies to inhibit VEGF pathway signaling.Notes: (A) anti-VEGF antibody (eg, bevacizumab); (B) anti-VEGFR-2 antibody (eg, ramucirumab); (C) soluble VEGF receptors (eg, aflibercept); and (D) VEGF receptor tyrosine kinase inhibitors (eg, sunitinib, sorafenib, regorafenib, apatinib [anti-VEGFR-2 TKI]).Abbreviations: Ab, antibody; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Mentions: Inducing angiogenesis to support the tumor-associated neovasculature is considered a key hallmark of cancer.36 The VEGFs that mediate these proangiogenic effects are homodimeric glycoproteins that include VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor.37,38 The angiogenic process is complex and involves the interaction between VEGF and its receptors including VEGF-1, VEGF-2, and VEGF-3. VEGFR-2 is a type II cell surface transmembrane kinase receptor that is mainly expressed on vascular endothelial cells.39 Binding of VEGF to VEGFR-2 results in phosphorylation and activation of multiple downstream pathways, activating a signaling cascade which promotes tumor angiogenesis.40 Despite a tenfold lower binding affinity of VEGF-A to VEGFR-2 compared to VEGFR-1, VEGFR-2 is considered to be the main driver of angiogenesis because the phosphorylated downstream targets are more potent signaling intermediaries.39,41 Therefore, it has been a key target for drug development. The VEGF pathway has also been closely investigated to help identify potential therapeutic strategies that may inhibit angiogenesis and tumor growth in order to develop new treatments. Strategies developed to inhibit the VEGF pathway are shown in Figure 1 and include anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, pazopanib, sorafenib, regorafenib), inhibitors of VEGFR-2 tyrosine kinases (eg, apatinib), and anti-VEGFR antibody therapy (eg, ramucirumab). Currently approved anti-angiogenic agents for various tumor types including lung, renal, and colon cancers include bevacizumab, sunitinib, pazopanib, and sorafenib. Increased expression of VEGF in tumor and serum has been shown in gastric cancer which is associated with poor prognosis and more aggressive disease.42,43 This suggests that angiogenesis may be an important target for gastric cancer and that inhibitors of the VEGF pathway may be a useful anti-tumor strategy.


Clinical utility of ramucirumab in advanced gastric cancer.

Chan MM, Sjoquist KM, Zalcberg JR - Biologics (2015)

Strategies to inhibit VEGF pathway signaling.Notes: (A) anti-VEGF antibody (eg, bevacizumab); (B) anti-VEGFR-2 antibody (eg, ramucirumab); (C) soluble VEGF receptors (eg, aflibercept); and (D) VEGF receptor tyrosine kinase inhibitors (eg, sunitinib, sorafenib, regorafenib, apatinib [anti-VEGFR-2 TKI]).Abbreviations: Ab, antibody; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4589126&req=5

f1-btt-9-093: Strategies to inhibit VEGF pathway signaling.Notes: (A) anti-VEGF antibody (eg, bevacizumab); (B) anti-VEGFR-2 antibody (eg, ramucirumab); (C) soluble VEGF receptors (eg, aflibercept); and (D) VEGF receptor tyrosine kinase inhibitors (eg, sunitinib, sorafenib, regorafenib, apatinib [anti-VEGFR-2 TKI]).Abbreviations: Ab, antibody; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
Mentions: Inducing angiogenesis to support the tumor-associated neovasculature is considered a key hallmark of cancer.36 The VEGFs that mediate these proangiogenic effects are homodimeric glycoproteins that include VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor.37,38 The angiogenic process is complex and involves the interaction between VEGF and its receptors including VEGF-1, VEGF-2, and VEGF-3. VEGFR-2 is a type II cell surface transmembrane kinase receptor that is mainly expressed on vascular endothelial cells.39 Binding of VEGF to VEGFR-2 results in phosphorylation and activation of multiple downstream pathways, activating a signaling cascade which promotes tumor angiogenesis.40 Despite a tenfold lower binding affinity of VEGF-A to VEGFR-2 compared to VEGFR-1, VEGFR-2 is considered to be the main driver of angiogenesis because the phosphorylated downstream targets are more potent signaling intermediaries.39,41 Therefore, it has been a key target for drug development. The VEGF pathway has also been closely investigated to help identify potential therapeutic strategies that may inhibit angiogenesis and tumor growth in order to develop new treatments. Strategies developed to inhibit the VEGF pathway are shown in Figure 1 and include anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, pazopanib, sorafenib, regorafenib), inhibitors of VEGFR-2 tyrosine kinases (eg, apatinib), and anti-VEGFR antibody therapy (eg, ramucirumab). Currently approved anti-angiogenic agents for various tumor types including lung, renal, and colon cancers include bevacizumab, sunitinib, pazopanib, and sorafenib. Increased expression of VEGF in tumor and serum has been shown in gastric cancer which is associated with poor prognosis and more aggressive disease.42,43 This suggests that angiogenesis may be an important target for gastric cancer and that inhibitors of the VEGF pathway may be a useful anti-tumor strategy.

Bottom Line: Prognosis remains poor with most patients presenting with advanced or metastatic disease.A better understanding of angiogenesis has led to the investigation of drugs that inhibit the vascular endothelial growth factor (VEGF) pathway including anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, sorafenib, apatinib, regorafenib), and inhibitors of vascular endothelial growth factor receptors (VEGFRs) (eg, ramucirumab).Ramucirumab, a VEGFR-2 inhibitor, is the first anti-angiogenic agent approved by the US Food and Drug Administration for use in the treatment of advanced gastric cancers.

View Article: PubMed Central - PubMed

Affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia ; Department of Medical Oncology, Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, Australia.

ABSTRACT
Gastric cancer is currently the third most common cause of cancer deaths worldwide. Prognosis remains poor with most patients presenting with advanced or metastatic disease. A better understanding of angiogenesis has led to the investigation of drugs that inhibit the vascular endothelial growth factor (VEGF) pathway including anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, sorafenib, apatinib, regorafenib), and inhibitors of vascular endothelial growth factor receptors (VEGFRs) (eg, ramucirumab). Ramucirumab, a VEGFR-2 inhibitor, is the first anti-angiogenic agent approved by the US Food and Drug Administration for use in the treatment of advanced gastric cancers. This review will focus on the clinical utility and potential use of ramucirumab in advanced gastric cancer.

No MeSH data available.


Related in: MedlinePlus