Development of angiogenesis inhibitors to vascular endothelial growth factor receptor 2. current status and future perspective

Paz, Keren; Zhu, Zhenping

doi:10.2741/1629

Cited by 55 publications

(33 citation statements)

References 169 publications

(222 reference statements)

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“…The median number of treatment cycles ranged from one to five, across the three non-continuous phase I trials, and the maximum number of cycles received by any patient was 30 (100 mg bid group, 7 days on/7 days off). In these three trials, patients received a median of either three or four treatment cycles (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14] at the MTD of 400 mg bid. There was no clear dose-dependent decrease in the number of cycles that patients received, up to 600 mg bid.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…Overactivation of receptor tyrosine kinases (RTKs), such as vascular endothelial growth factor receptor (VEGFR)-2/-3, platelet-derived growth factor receptor (PDGFR)-␤, and epidermal growth factor receptor (EGFR), as a result of either activating mutations or overexpression of their growth factor ligands, can result in aberrant signaling through Raf, dysregulated cell growth, and cancer [1,2,10]. Aberrant signaling through VEGFR-2 is associated with neoangiogenesis [11] and melanoma progression [12], whereas overexpression of VEGFR-3 occurs in vascular skin tumors and invasive breast carcinoma microvasculature [13]. Oncogenic mutations that lead to aberrant activation of PDGFR-␤ occur in myeloid leukemias and gastrointestinal stromal tumors (GISTs) [14].…”

Section: Introductionmentioning

confidence: 99%

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Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Sorafenib: A Review of Four Phase I Trials in Patients with Advanced Refractory Solid Tumors

Strumberg¹,

et al. 2007

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LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe the mechanisms of action of sorafenib.2. Discuss the safety and toxicity data from phase I trials of sorafenib.3. Evaluate phase I and II trials of sorafenib with activity data. 4. Discuss future areas for research in the development of this drug.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTSorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n ‫؍‬ 173). These trials followed different treatment regimens (7 days on/7 days off, n ‫؍‬ 19; 21 days on/7 days off, n ‫؍‬ 44; 28 days on/7 days off, n ‫؍‬ 41; or continuous dosing, n ‫؍‬ 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drugrelated adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer. The Oncologist 2007;12: 426 -437 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Safety and Tolerabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Sorafenib: A Review of Four Phase I Trials in Patients with Advanced Refractory Solid Tumors

Strumberg¹,

et al. 2007

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“…This antibody specifically binds VEGFR-2 with an affinity of 50 pmol/L, and at 1 nmol/L, it results in 50% inhibition of the interactions between VEGF and VEGFR-2. In addition, it strongly inhibits VEGF-induced migration of human leukemia cells in vitro and, when administered in vivo, significantly prolongs the survival of immunodeficient mice inoculated with VEGFR-2 -expressing human leukemia cells (7,15). Phase I clinical trials of IMC-1121B are currently in progress in patients with advanced malignancies.…”

Section: Clinical Progress Of Anti-vegfr-2 Antibodiesmentioning

confidence: 99%

“…IMC-1121B is a second-generation, fully human anti-VEGFR-2 IgG1 antibody that currently is in clinical development (7,15). This antibody specifically binds VEGFR-2 with an affinity of 50 pmol/L, and at 1 nmol/L, it results in 50% inhibition of the interactions between VEGF and VEGFR-2.…”

Section: Clinical Progress Of Anti-vegfr-2 Antibodiesmentioning

confidence: 99%

“…Four tyrosine residues, Tyr 951 , Tyr 996 , Tyr 1054 , and Tyr 1059 , represent critical autophosphorylation sites and serve as high-affinity docking sites for a variety of signaling proteins, including phospholipase Cg, Ras-GAP, focal adhesion kinase, Src family of tyrosine kinases, phosphoinositide 3-kinase, Akt, protein kinase C, Raf-1, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. The interaction of one or more of these molecules with VEGFR-2 may then lead to alterations in cell proliferation, migration, differentiation, tube formation, increase in vascular permeability, and vascular integrity (7,15).…”

Section: Vegfr-2 Expression and Functionmentioning

confidence: 99%

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Review: Monoclonal Antibodies to the Vascular Endothelial Growth Factor Receptor-2 in Cancer Therapy

Youssoufian¹,

Hicklin²,

Rowinsky³

2007

Clinical Cancer Research

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Angiogenesis is a fundamental mechanism of cancer growth and invasion. Current translational approaches are using both small-molecule inhibitors and antibodies that modulate various steps of these processes, and several such compounds have already received regulatory approval for the therapy of specific indications in cancer. Among the many molecular targets involved in the control of angiogenesis, the vascular endothelial growth factor receptor-2 (VEGFR-2; or kinase insert domain-containing receptor) is attractive as shown in part by the efficacy of small-molecule inhibitors directed to this receptor. Two small-molecule inhibitors that target VEGFR-2 have recently been granted approval for the treatment of renal cell cancer and gastrointestinal stromal tumors. The development of antibodies that can selectively block VEGFR-2 could potentially result in improved potency or tolerability. Here, we discuss the role of VEGFR-2 in cancer and ongoing efforts to develop highly specific monoclonal antibodies for cancer therapy.

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Development of antibody-based therapeutics for oncology indications

Li¹,

Zhu²

2006

Drug Dev. Res.

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Monoclonal antibodies have emerged as novel oncology therapeutics. These biologics exert anticancer effects via a variety of mechanisms of action including modulating the function of key regulatory molecules and signaling pathways of tumor cells such as blocking growth factor/receptor interaction and/or down-regulating expression of oncogenic proteins (e.g., growth factor receptors) on the cell surface; recruiting effector mechanisms of the immune system, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity; as a targeting device in immnuoconjugates; and other mechanisms such as anti-idiotype, catalytic antibodies, or antibodies that modulate patient's immune responses to tumors. In this review, we focus on the research and development experience of four such representative antibody therapeutics, rituximab (Rituxan s ), trastuzumab (Herceptin s ), cetuximab (Erbitux s ), and bevacizumab (Avastin s ), approved for treating non-Hodgkin's lymphoma, metastatic breast cancer, and colorectal cancer, respectively. The biology behind each antibody target, their proposed mechanisms of action, as well as preclinical and clinical development of these antibodies are the topics of this article. Experience drawn from the development process of these four antibodies is instrumental for ongoing and future antibody development activities. In addition, perspective views on challenges and opportunities of oncology antibody therapeutics are presented. Drug Dev. Res. 67: 699-728, 2006.

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Development of angiogenesis inhibitors to vascular endothelial growth factor receptor 2. current status and future perspective

Cited by 55 publications

References 169 publications

Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Sorafenib: A Review of Four Phase I Trials in Patients with Advanced Refractory Solid Tumors

Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Sorafenib: A Review of Four Phase I Trials in Patients with Advanced Refractory Solid Tumors

Review: Monoclonal Antibodies to the Vascular Endothelial Growth Factor Receptor-2 in Cancer Therapy

Development of antibody-based therapeutics for oncology indications

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