Pazopanib: a new multiple tyrosine kinase inhibitor in the therapy of metastatic renal cell carcinoma and other solid tumors.

ABSTRACT

Angiogenesis plays a crucial role in tumor progression. Tumor angiogenesis is driven by host-derived circulating factors. Prominent among these factors is vascular endothelial growth factor (VEGF). Two basic approaches have been pursued in therapies targeting VEGF neutralization of VEGF by antibodies or inhibition of VEGF receptor (VEGFR). VEGFR inhibition has relied on the use of small-molecular inhibitors. These drugs inhibit the tyrosine kinase activity of VEGFRs as well as other tyrosine kinases, and the term tyrosine kinase inhibitor (TKI) is used to describe this class of drugs. Pazopanib (GW786034), N(4)-(2,3-dimethyl-2H-indazol-6-yl]-N(4) - methyl-N(2)-(4-methyl-3-sulfnonamidophenyl)-2,4-pyrimidinediamine, is a novel orally bioavailable TKI that targets VEGFR1, VEGFR3, platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-kit. Activity was observed in early clinical testing, specifically in patients with metastatic renal cell carcinoma (RCC). In subsequent phase II and phase III trials, the activity of pazopanib was comparable to other targeted agents used in the first-line therapy of metastatic RCC. Promising activity was reported in a number of other tumors, including metastatic carcinoma of the uterine cervix and differentiated carcinomas of the thyroid.