Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Abstract

Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed.

Figure 1.

Dysregulated signaling through Raf-1 in tumor cells, endothelial cells, and/or pericytes could result in tumor growth and/or angiogenesis by an autocrine mechanism in RCC.

Figure 2.

Sorafenib inhibits the growth of s.c. implanted human 786-O and murine Renca RCC tumors (adapted from refs. 42, 66). A, female athymic NCr nu/nu mice were implanted s.c. with 786-O tumor fragments or Renca cells. Sorafenib or vehicle control was administered orally, once a day, for 21 d (786-O) or 9 days (Renca) at the indicated dose. n = 10 per group. ^‡, P < 0.001. B, sorafenib reduced CD34 but did not alter pERK level in 786-O tumors. Treatment began when tumors reached a volume of 200 to 400 mm (3). Sorafenib and vehicle control were administered orally, once a day, for 5 d at the indicated dose. Tumors were collected and then immunostained with anti-CD34 or anti-pERK antibody. C, level of CD34 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling in the 786-O tumors was evaluated on images captured using bright-field microscopy. Average of more than 10 random tumor sections taken from three different tumor samples.

Figure 3.

Sorafenib strongly inhibits the growth of PLC/PRF/5 HCC tumors in a xenograft mouse model (adapted from ref. 35). A, in vivo efficacy of sorafenib dosed orally, once a day, for 14 or 21 d. B, sorafenib decreases pERK and CD34 level and induces cell death in PLC/PRF/5 HCC tumors in mice. Tumors were collected and then immunostained with anti-pERK or anti-CD-34 antibody. C, sorafenib significantly inhibits MVA (CD34) in PLC/PRF/5 HCC tumors in mice. MVA and microvessel density were plotted.

Figure 4.

Effect of sorafenib on growth of (A) Colo-205 and (B) HT-29 human colon carcinoma xenografts [adapted from Wilhelm et al. (27)]. In vivo efficacy of sorafenib dosed orally, once a day, for 9 d. C, Western blot analysis using anti-pERK and anti-ERK antibodies. D, treatment with sorafenib inhibited tumor growth without substantially reducing MAPK activation in Colo-205 xenografts. E, tumors were collected and then immunostained with anti-CD31 antibody. MVA and microvessel density were plotted. Mice with tumors measuring 100 to 200 mg received 5 d of sorafenib treatment.