An overview of small-molecule inhibitors of VEGFR signaling

被引：295

作者：

Ivy, S. Percy ^{[1
]}

Wick, Jeannette Y. ^{[2
]}

Kaufman, Bennett M. ^{[3
]}

机构：

[1] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA

[2] NCI, Pharmaceut Management Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA

[3] PSI Int Inc, Fairfax, VA USA

来源：

NATURE REVIEWS CLINICAL ONCOLOGY | 2009年 / 6卷 / 10期

关键词：

ENDOTHELIAL-GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; ADVANCED SOLID TUMORS; VASCULAR-PERMEABILITY FACTOR; ORALLY-ACTIVE INHIBITOR; FOCAL ADHESION KINASE; HIPPEL-LINDAU-DISEASE; I DOSE-ESCALATION; PHASE-I; ANTITUMOR-ACTIVITY;

D O I：

10.1038/nrclinonc.2009.130

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure-activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.

引用

页码：569 / 579

页数：11

共 98 条

[1] Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells [J].

Abedi, H ;

Zachary, I .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (24) :15442-15451

[2] Role of tyrosine kinase inhibitors in cancer therapy [J].

Arora, A ;

Scholar, EM .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 315 (03) :971-979

[3] Oncogenic kinase signalling [J].

Blume-Jensen, P ;

Hunter, T .

NATURE, 2001, 411 (6835) :355-365

[4]

Boyer Stephen J., 2002, Current Topics in Medicinal Chemistry, V2, P973, DOI 10.2174/1568026023393273

[5] Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane [J].

Burstein, Harold J. ;

Elias, Anthony D. ;

Rugo, Hope S. ;

Cobleigh, Melody A. ;

Wolff, Antonio C. ;

Eisenberg, Peter D. ;

Lehman, Mary ;

Adams, Bonne J. ;

Bello, Carlo L. ;

DePrimo, Samuel E. ;

Baum, Charles M. ;

Miller, Kathy D. .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (11) :1810-1816

[6] VEGF as a key mediator of angiogenesis in cancer [J].

Carmeliet, P .

ONCOLOGY, 2005, 69 :4-10

[7] Angiogenesis in life, disease and medicine [J].

Carmeliet, P .

NATURE, 2005, 438 (7070) :932-936

[8] von Hippel-Lindau disease: Clinical and molecular perspectives [J].

Clifford, SC ;

Maher, ER .

ADVANCES IN CANCER RESEARCH, VOL 82, 2001, 82 :85-105

[9] The development and therapeutic potential of protein kinase inhibitors [J].

Cohen, P .

CURRENT OPINION IN CHEMICAL BIOLOGY, 1999, 3 (04) :459-465

[10] A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC) [J].

Cohen, Roger B. ;

Langer, Corey J. ;

Simon, George Rajan ;

Eisenberg, Peter David ;

Hainsworth, John Daniel ;

Madajewicz, Stefan ;

Cosgriff, Thomas Michael ;

Pierce, Kristen ;

Xu, Huiping ;

Liau, Katherine ;

Healey, Diane .

CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2007, 60 (01) :81-89

← 1 2 3 4 5 6 7 8 9 10 →