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Keith T. Flaherty
Sorafenib is an orally available inhibitor of vascular endothelial growth factor receptors, plateletderived growth factor receptor-h, and RAF kinases. A dose of 400 mg twice daily administered continuously was selected for phase 2 testing, although 600 mg twice daily formally met criteria for a maximum tolerated dose. It is well tolerated compared with cytokine therapy. Antitumor activity was shown clearly in the context of a randomized discontinuation phase 2 trial. In this setting, even disease stabilization was established as a treatment-related phenomenon. A phase 3 trial with sorafenib confirmed a benefit of therapy across the vast majority of patients treated with sorafenib as opposed to placebo. Limited investigations into the mechanism of action of sorafenib in renal cell carcinoma support vascular endothelial growth factor receptor antagonism as the primary mediator of effect. The toxicity profile of sorafenib allows for its use in combination regimens.The focus of efforts to improve on the efficacy of sorafenib is on use with IFN, bevacizumab, or temsirolimus. Preliminary evidence with this approach is promising and will be the subject of the next generation of randomized trials in renal cell carcinoma.
Recently approved by the Food and Drug Administration, sorafenib (Bayer Pharmaceuticals, West Haven, CT) is an agent with established single-agent efficacy in metastatic renal cell carcinoma (RCC). It is among 17 inhibitors of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2 (VEGFR2 or KDR) in clinical testing. However, the spectrum of kinase inhibition offered by sorafenib differentiates it from other agents and deserves consideration (Table 1). The unique clinical development path of sorafenib has uncovered some properties of the agent that may contribute to further advances in RCC treatment. In this review, we consider the important preclinical, clinical, and translational data that support the efficacy of sorafenib and the avenues for further clinical investigation.
Sorafenib was initially identified as a potent inhibitor of c-RAF. When hypertension was observed in the context of phase 2 trials, sorafenib was hypothesized to be a VEGFR inhibitor. Biochemical assays established that it is a potent inhibitor of VEGFR2 and VEGFR3. Both of these transmembrane receptors are implicated in tumor pathophysiology (Fig. 1). VEGFR2, previously referred to as KDR, is one of two high-affinity receptors for VEGF-A (VEGF165; ref. 1). Transgenic mice lacking VEGFR2 do not survive embryogenesis and have impaired
Author’s Affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania Received 8/17/06; revised 11/7/06; accepted 11/10/06. Presented at the Second Cambridge Conference on Innovations and Challenges in Renal Cancer, March 24-25, 2006, Cambridge, Massachusetts. Requests for reprints: Keith T. Flaherty, Abramson Cancer Center, University of Pennsylvania, 51North 39th Street, MAB 103, Philadelphia, PA 19104. Phone: 215662-8624. E-mail: ktflaherty@ aol.com. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-2063
blood vessel formation (2). Selective disruption of the VEGF-A/ VEGFR2 interaction is associated with tumor growth inhibition in human tumor xenografts in mice (3). The importance of VEGFR1 in VEGF-A – mediated angiogenesis is less clear because abrogation of the kinase activity of VEGFR1 does not affect vessel formation in transgenic mice (4). VEGFR3 has been identified as a high-affinity receptor for VEGF-C and VEGF-D, which mediate lymphangiogenesis (5). Tumor metastasis via lymphatics can be inhibited by interference with the VEGF-C VEGFR3 interaction (6). Thus, activity against VEGFR2 and VEGFR3 in a disease that is VEGF driven, such as RCC, is an attractive feature of sorafenib. Platelet-derived growth factor (PDGF) receptor-h has been the focus of several recent preclinical investigations and seems to be a valid target for angiogenesis inhibition. In addition to VEGF, hypoxia also induces secretion of PDGF (7). PDGF and PDGF receptor expressions are up-regulated in microvessel endothelial cells compared with mature vessels (8). Signaling through the PDGF receptor pathway in pericytes is essential for their recruitment (9, 10). In turn, the recruitment of pericytes is essential to the maturation and stabilization of immature blood vessels (11). Microvessels that are endowed with pericytes are no longer dependent on VEGF for their survival (12). Similar to the role of VEGF as a survival factor for immature endothelial tubes, under hypoxic conditions, pericytes are dependent on PDGF for survival (13). Inhibition of PDGF, in the absence of VEGF inhibition, inhibits blood vessel formation and tumor growth in human tumor xenografts (14). In an animal model of pancreatic islet cell tumors, the dual inhibition of VEGF and PDGF seems to be markedly more effective at blocking angiogenesis than blockade of either alone (15). Several lines of evidence suggest that inhibition of RAF signaling inhibits angiogenesis. In cells that overexpress the VEGF receptor, flk-1/KDR, VEGF signaling through the RAF –mitogenactivated protein kinase/extracellular signal-regulated kinase kinase – mitogen-activated protein kinase pathway is necessary for proliferation (16). In endothelial cells, VEGF-induced
Clin Cancer Res 2007;13(2 Suppl) January 15, 2007
Consideration of other cancers. none of the 15 treated at 400 mg twice daily. This trial used modified WHO response criteria to avoid randomizing patients with clinically significant reductions in tumor volume. Eligibility was not restricted based on histologic subtype or number of prior therapies. Sorafenib targets in tumor cells. and the median number of prior therapies was 2. Although it is reasonable to infer that the 600 mg dose level was intolerable based on a 29% dose-limiting toxicity rate. (18) have developed a nanoparticle delivery system that specifically targets tumor endothelium. In that study. and pericytes. EGFR. and hand-foot syndrome. Of the 202 RCC patients enrolled. inhibition of mitogen-stimulated RAF activity was observed in peripheral mononuclear cells. when other toxicities. and fatigue. Therefore. The clinical development of sorafenib is notable for the large randomized discontinuation phase 2 trial. It should be noted that in vitro. 600. mitogenactivated protein kinase/extracellular signal-regulated kinase kinase. This last group of Fig. Clin Cancer Res 2007. meeting criteria for a conventional objective response. incapable of binding ATP. Although it still difficult to discern which of the targets of sorafenib might be mediating this effect. 2007 748s www. such as melanoma. is beyond the scope of this review. PDGFR-h FLT-3. if not as a starting dose. MEK. PKC. Considering all grades of toxic effects. 2). sunitinib. Sorafenib is one of the few toxicities that emerges relatively late in the course of treatment. such as RAF. Most patients had clear cell RCC. hand-foot syndrome. and then after 2 months of therapy with 400 mg. activation of mitogen-activated protein kinase is inhibited by expression of a truncated form of RAF that binds to Ras but cannot phosphorylate mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase (17). ERK. Nonetheless. This leads one to speculate that a unique target of sorafenib. to tumor endothelium results in inhibition of angiogenesis and tumorassociated endothelial cell apoptosis. PKC. Coupling of an integrin 3 ligand to the surface of nanoparticles results in selective trafficking of particles to angiogenic blood vessels in tumor-bearing mice. and 3 of 6 at 800 mg twice daily. and other small-molecule inhibitors of VEGFR and PDGF receptor. Dose-limiting toxicity was observed in 1 of 6 patients treated at 200 mg twice daily. Pruritus is exclusively present in the setting of rash. sorafenib inhibits the proliferation of RCC cell lines. It is possible to link some of the common sorafenibassociated toxicities with known molecular targets by comparing the toxicities seen with other targeted therapies with overlapping spectrum of activity.aacrjournals. might mediate this effect. investigating distinct schedules of administration: three with interrupted dosing and one with continuous administration (20). MEK. direct tumor cytotoxicity may be a component of the clinical efficacy observed in RCC. According to the modified WHO criteria used in the protocol.13(2 Suppl) January 15. extracellular signal-regulated kinase. endothelial cells. epidermal growth factor receptor. diarrhea. 11% of patients had 50% regression by WHO criteria. 1. Sorafenib was evaluated in four phase 1 trials. it is difficult to determine the relative contribution of each sorafenib target to the antitumor activity. Given that it has been the only RAF kinase inhibitor to be evaluated clinically. are relatively unique to sorafenib and could be implicated in any of the toxicities that are unique to this agent.Table 1. The most common moderate or severe toxic effects were rash. 400 mg twice daily was selected for further development. where BRAF harbors activating mutations and might serve a more definitive test of sorafenib RAF-inhibitory properties. The macular-papular rash associated with sorafenib is not commonly observed with bevacizumab (a VEGF antibody). These data support the necessity of RAF activity in the VEGF-induced activation of endothelial cells. an experimental system that is independent of angiogenesis. the three toxic effects that were clearly treatment related were rash. VEGFR3 WT BRAF. diarrhea. 36% had tumor regressions of at least 25% and 32% had regression or progression of <25%. V599E BRAF p38. ERK IC50 2 nmol/L 6-10 nmol/L 20-40 nmol/L 28-38 nmol/L 40-80 nmol/L Inactive at 10 mmol/L Abbreviations: PDGFR-h. it is possible that longterm therapy at 600 mg twice daily is feasible. in which activity in RCC was first observed (21). Pharmacokinetic data support the selection of this dose because exposure did not increase significantly between cohorts treated with 400. Spectrum of sorafenib in isolated kinase assays Kinase assays c-RAF mVEGFR2. protein kinase C. grade 3 events were infrequent. Phase 2 and 3 trials. the agent clearly affects the maintenance of tumor vasculature and angiogenesis (19). and 800 mg. This time course makes one wonder if this is less likely a signal transduction effect on intestinal epithelial cells and perhaps more related to chemical irritation from the carriers in the formulation. PDGF receptor-h.org . have dissipated. most patients experience a decline in toxic effects after the first 4 to 6 weeks of treatment. At doses of 200 mg twice daily and higher. Hood et al. Hypertension is class effect of essentially all VEGF-targeted therapies and is discussed in detail below. Clinical Data Phase 1 and toxicity. Delivery of a mutant RAF gene. such as rash. The phase 3 trial comparing sorafenib to placebo in cytokinerefractory RCC provides the best summary of sorafenib-related toxic effects at 400 mg twice daily (Fig. it is difficult to verify this point. This is associated with apoptosis of tumor cells and prolonged regression of primary and metastatic tumors. Other targets. c-KIT EGFR. 4 of 14 at 600 mg twice daily. Nonetheless. such as p38. In vivo.
018). 3. 2007 . relatively large tumors are needed (>3 cm in some cases) to obtain robust measurements of K tr. This can be quantified by comparing the area under the time-enhancement curves before and during treatment. Nine hundred three patients with clear cell RCC refractory to one prior therapy were enrolled. this marker of otherwise poor prognosis seems to identify those most likely to receive clinical benefit. due to the related observation that many metastatic RCC lesions develop radiographically evident necrosis while on sorafenib therapy. 95% confidence interval. P < 0. this small pilot study will require validation in a larger trial. this trial established clinical activity in most patients. Taken together with the patients with tumor regression (median PFS. 60. in part. We conducted a pilot study using dynamic contrast-enhanced magnetic resonance imaging as a method of detecting changes in tumor vascular permeability (K tr. Therefore. and interpreting the results requires a significant amount of expertise. The significant difference in PFS (median. In the setting of VEGF inhibition. This is. Although dynamic contrast-enhanced magnetic resonance imaging can assess metastatic tumors in a variety of metastatic sites. Thus. both adverse prognostic signs in RCC. 23). The comparison of progression-free survival (PFS) in this cohort was the primary end point of the study. www. The median PFS (5. 3). 0. We have observed that serum VEGF levels increase during the initial weeks of therapy with sorafenib. Although this study was designed to compare overall survival. grade 3). In addition. Of note. gadolinium diffusion into tumors is reduced.6%).8 months.72.0087) confirmed that disease stabilization was attributable to sorafenib. those who had a doubling or more in serum VEGF had a more Fig. 2. Given that some tumors develop macroscopic evidence of necrosis.org 749s Clin Cancer Res 2007. elevated K tr at baseline was significantly correlated with time-to-progression (P = 0. P = 0.00001) for sorafenib was nearly identical to that observed in the phase 2 trial (Fig. Progression-free survival Kaplan-Meier analysis in Phase III renal cell carcinoma trial. P = 0.13(2 Suppl) January 15. Of course. Correlative studies. The phase 3 trial of sorafenib in RCC used a more conventional one-to-one randomization at the time of study entry to sorafenib versus placebo. This technique takes advantage of the influence of VEGF on vascular permeability and has been validated in preclinical models. This cutpoint was chosen based on the equal distribution of patients above and below this value. Among 17 patients with varied RCC histologic subtypes. Gadolinium diffuses across tumor vasculature more readily than normal vessels.22). as it is seen even among people without cancer.Sorafenib in RCC Fig. 48% of the patients initially assigned to placebo crossed over to sorafenib soon after the PFS analysis. An interim analysis for overall survival revealed a nonsignificant trend toward improved survival (hazard ratio. Previous studies in patients with other tumor types have correlated elevated K tr with high microvessel density and serum VEGF levels. patients (n = 65) were randomized to continue sorafenib or cross over to placebo.0005 was required to yield a definitive benefit. The antiangiogenic activity of sorafenib in vivo has been investigated in the context of the large phase 2 trial of sorafenib. reduction in K tr significantly correlated with prolonged time-toprogression (P = 0. This will happen in the context in the E2804 (to be discussed later).02). 4. each of these variables was treated as continuous. 46.01) but not with the amount of tumor regression by computed tomography (P = 0. Although these patients continue to be followed up for overall survival. The investigator-assessed objective response rate was 10% by Response Evaluation Criteria in Solid Tumors criteria. the objective response rate does not adequately summarize the effect of sorafenib on the natural history of metastatic RCC.5 versus 2. K tr was significantly lower after sorafenib treatment (median. we did baseline dynamic contrast-enhanced magnetic resonance imaging and a followup assessment after several weeks of therapy. This will undoubtedly limit the statistical power to detect a survival advantage for sorafenib. grey bar.aacrjournals. Frequency of symptomatic toxicities in Phase III renal cell carcinoma trial (black bar. and the trial was terminated prematurely with placebo-treated patients crossed over to sorafenib (22). P < 0. This is not a tumorrelated phenomenon but rather a systemic response to VEGF blockade. in the context of sorafenib therapy. it is possible that K tr is detecting this type of effect and that changes in tumor size are somewhat independent.1-74. The Kaplan-Meier PFS for patients with baseline K tr > 3 mL/mL/min and baseline K tr < 3 mL/mL/min is shown in Fig. the first interim analysis for PFS was revealed to the investigators. identification of a serum marker of pharmacodynamic effect would be preferable. 24 versus 6 weeks. This seems to be a class phenomenon for the VEGF-targeted agents in this disease. Unexpectedly. Clearly. any CTC grade. Among a cohort of 20 patients treated with sorafenib. patients must at least undergo imaging studies beyond those required for clinical staging. 40 weeks). ref. As hypothesized.3% decline.
Conclusions Sorafenib has established efficacy in RCC and is well tolerated. we conducted an investigation of the mechanism of sorafenib-induced hypertension in patients with metastatic RCC (24). it is hypothesized that targeting multiple angiogenic growth factors will yield even greater benefits in RCC. the number of potential combination regimens multiplies. Open Discussion Dr. temsirolimus (CCI-779. South San Francisco. transforming growth factors a and h. However. the development of new areas of tumor necrosis within tumors. 4. We observed a consistent elevation in blood pressure for the entire cohort (Fig. This is a class effect observed not only with VEGFR inhibitors but also with the VEGF monoclonal antibody. Although we have observed that increases in VEGF correlate with clinical benefit. the target of temsirolimus. The combination of sorafenib and bevacizumab is in the midst of phase 1 evaluation. sorafenib will be combined with bevacizumab and temsirolimus. may be evidence of greater degrees of tumor hypoxia. Assessment of vascular permeability (Ktr) by DCE-MRI correlated with PFS or sorafenib (N = 17). The spectrum of kinases inhibited by sorafenib goes far beyond VEGFRs and is unique compared with other agents in this class. In addition to bevacizumab. basic fibroblast growth factor. Clin Cancer Res 2007. Sorafenib in combination regimens. By down-regulating hypoxia-inducible factor 1-a in the tumor cell. This will be the focus of investigations in the next generation of clinical trials. In particular. which has been shown previously to be VEGF mediated (25). Sorafenib is sufficiently tolerable to be combined with other agents. epidermal growth factor. we are initiating a randomized phase 2 trial in the cooperative groups (E2804). Collegeville. This is supported by the rapid normalization of blood pressure following interruption of sorafenib. The contribution of these various targets to the activity of sorafenib in RCC is not known. 2007 750s www. In addition. Changes in serum VEGF while on sorafenib correlate with PFS. The combination of sorafenib and temsirolimus is being evaluated in a phase 1 trial. which is up-regulated by the loss of the von Hippel Lindau gene in RCC. sorafenib is well suited to inclusion in combination regimens. The armamentarium of targeted agents against these factors is limited. A more thorough evaluation of the blood pressure as a potential marker of VEGF inhibition is warranted.Fig. which is manifested on computed tomography scans. One combination of particular interest is simultaneous blockade of VEGFRs with depletion of secreted VEGF. There are several potential explanations for this relationship. Greater increases in VEGF levels in the setting of VEGFR blockade may simply relate to higher drug exposure. A thorough analysis of the relation between changes in blood pressure and outcome has not been reported. temsirolimus may complement the effects of sorafenib at the level of the endothelial cell. and interleukin 8 have all been implicated in tumor angiogenesis (26). PA) is another agent that seems to affect angiogenesis at a point that is different from sorafenib. This threshold was selected based on nearly even numbers of patients above and below this value. In that study. Angiogenesis is mediated by other factors in addition to VEGF and PDGF. including sorafenib. The rationale behind this approach is founded on the observation that serum VEGF levels increase following administration of VEGFR inhibitors. For that reason. it remains possible that increased VEGF production eventually mediates resistance to therapy. 6). We found no significant relationship between previously described mediators of blood pressure and magnitude of increase. Based on its toxicity profile and target spectrum. 5. triggering more VEGF production. Bevacizumab (Genentech. Although we could not measure it directly. Figlin: Is it possible that the vascular endothelial growth factor (VEGF) receptor antagonists are working best on the hypoxic environment of VEGF-dependent tumors and are not working well on the VHL-dependent tumor in the outer rim? Fig. we suspect that sorafenib is inhibiting nitric oxide production in endothelial cells. favorable outcome than those with little or no change in VEGF (Fig.aacrjournals. Mammalian target of rapamycin. In an effort to evaluate the currently available agents as doublets in parallel. CA) has been shown previously to deplete serum VEGF to undetectable levels at doses of 3 mg/kg and higher (27). 5). Wyeth Pharmaceuticals. regulates the expression of hypoxia-inducible factor 1-a (28).org . An even more convenient biomarker of sorafenib effect might be treatment-related hypertension.13(2 Suppl) January 15. The currently available evidence suggests that VEGFR antagonism is being achieved. As the number of targeted agents with relevance to RCC increases.
Rosen: Might the neovessels at the tumor rim and those at the tumor center behave differently—as they may not be at the same stage of maturation—even though they are all driven by the same angiogenic signals from the tumor? Dr. George: There may be different compartments to the vasculature: compartments that are immature. but that is not the case. a receptor for vascular endothelial growth factor. George: These are not homogeneous masses. the more heterogeneous. Makinen T.376:66 ^ 70. Overholser JP. Kuno J. Carmeliet P. With these agents. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. However. Kawamura H. J Pharmacol Exp Ther 2001. Blaskovich MA. Proc Natl Acad Sci U S A 1998.Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. 4. Jain RK. Nature1995. Stastny VA. such as platelet-derived growth factor. but I’ve never seen any data that quantify the percentage of. you do not have the normal tissue repair. Itin A. Kodama T. migration. we have all seen data. Dr. Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation. Circ Res 1999. Figlin: How does that explain how these drugs work in this disease? Dr. KarpanenT. 6. et al. Beck LH. The bigger they get. Benjamin LE. et al. Atkins: My hypothesis for hand-foot syndrome and mucositis is that those areas of the body are constantly undergoing subclinical trauma. Hemo I. References 1. et al. Hirschi KK. 125:1591 ^ 8. Oku H. Development 1991. for example. Egeblad M. 14. 5. Plateletderived growth factor-BB: a survival factor for the retinal microvasculature during periods of metabolic compromise. That is why it is harder to make those comments. Holmgren L. 8. Sukhatme: Is it true that the hypertension seen with this drug is actually less than what is seen with. Brekken RA. Wouldn’t this lead to rebound growth of RCC when VEGF receptor inhibitors are stopped abruptly? Dr. RossantJ. Alitalo K.407:249 ^ 57. Dr. Flaherty: Exactly. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. 9. Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression. Dr. I do not believe so. The fms-like tyrosine kinase. 7.4:E2 ^ 5. and perhaps compartments that are more complex with both VEGF-dependent components as well as components dependent on other growth factors. Keshet E. Ueno H. Is that really biologically important in terms of the population of patients? I know there have been anecdotes of patients having minor tumor progression during that 2-week break. Flt-1lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Cancer Res 2000. J Clin Invest 1999. Dr. 6. what factors do you think are responsible for those side effects? Dr.13(2 Suppl) January 15. Everyone believed 5 years ago that angiogenesis happened only in wound healing and after a myocardial infarction in adults. So. et al. Dr.84:298 ^ 305. et al. and suppression of neointima following vascular injury. Yu JC.Sorafenib in RCC Fig. Angiogenesis in cancer and other diseases. et al. Escobedo JA.23:93 ^ 7.255:989 ^ 91. a platelet-derived growth factor binding www. Flaherty: The rash didn’t correlate with progression-free survival. Flaherty: Yes. Flaherty: With SU11248. that when you block the VEGF receptor with tyrosine kinase inhibitors serum VEGF levels increase. 3. Hiratsuka S. Nat Cell Biol 2000. 2. we do not use intermittent dosing. et al.61:1786 ^ 90. the VEGF levels are clearly up on therapy. Flaherty: We’ve never compared bevacizumab and this drug in a rigorous way.298: 1172 ^ 78. et al. With sorafenib. Lin Q. GlaserA. and over time. Minowa O. Cancer Res 2001 . Gertsenstein M. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. The rash may be a RAF-driven phenomenon because it is different from the epidermal growth factor receptor rash. et al. et al. this lack of normal tissue repair causes either ulcerations at pressure points in the mouth or on the hands and feet. De Vries C. for example. Dr. You have angiogenesis that is part of minor levels of trauma that occur every day. 12. they’re down again to baseline. Role of the Flt-1receptor tyrosine kinase in regulating the assembly of vascular endothelium. Delarue FL. Dr. These inhibitors are probably only working on a subset of the tumor vasculature. McDermott: You said that you do not believe rebound is happening with this drug. 10. This is a small window of overdrive. but after the 2-week break. Rohovsky SA. 13. It might be there. To what extent we can add to them and optimize the antiangiogenic effect remains to be seen. Benjamin LE. The other potential explanation is that the fraction of VEGF-dependent neovessels is differentially present as you move through zones of the tumor. Nature 2000. tumor cells in the rim probably aren’t dependent on tumor vasculature entirely for delivery of blood and nutrients. Dr. Sosman: But the hand-foot syndrome is seen across the board with all the multitargeted tyrosine kinase inhibitors.aacrjournals. et al. Lymphatic endothelium: a new frontier of metastasis research. Pfeifer-Ohlsson S. Atkins: Was there any correlation between rash or hand-foot syndrome and clinical benefit? Of the targets that this drug is hitting. people who have blood pressure elevations over systolic of 150 mm Hg or some other significant threshold. 113:749 ^ 54. Dr. VEGF-dependent compartments. from you and others. Flaherty: One potential explanation is that the dependence of the rim on tumor vasculature to deliver nutrients and oxygen is different than the core.103:159 ^ 65. Mechanism of sorafenib-induced hypertension in patients with metastatic RCC. Curr Eye Res 2001 . A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. bevacizumab or in any of the early drugs on VEGF trial? Dr.95:9349 ^ 54. Golijanin D. Science 1992. Dr.18:5117 ^ 24. Karkkainen MJ. 2007 . Fong GH. Design of GFB-111. Hollenbach S. Karkkainen MJ.org 751s Clin Cancer Res 2007. 11. but to a degree that is not clinically meaningful. that’s seen with the other drugs as well. Development 1998. Lokker NA.
Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) [abstract LBA4510]. VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. J Clin Oncol 2004. Nature 1999. 17. Biochem Biophys Res Commun 1999. Regulation of hypoxia-inducible factor 1a expression and function by the mammalian target of rapamycin. Hudson CC. et al. Am J Physiol Heart Circ Physiol 2003. Bergers G. 18.22:4501. et al. Mechanisms of hypertension associated with BAY 439006. Wilhelm SM. J Clin Oncol 2006. et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.255:545 ^ 8. Ueno H. Tumor regression by targeted gene delivery to the neovasculature.org . J Clin Invest 2003.24:1363 ^ 9. Frausto R.Veronese ML.molecule with antiangiogenic and anticancer activity against human tumors in mice. Pharmacodynamic study of BAY 43-9006 in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 2005. Strumberg D. Breslin JW. 22. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Chiang GG. 2007 752s www. 19. Gallagher M. 23:965 ^ 72. Tang L.111:1287 ^ 95. Takahashi T. Flaherty KT. Wiesener MS. 15. Meyer-Morse N. Chang GW. 16. 18:1065 ^ 70.VEGF stimulates MAPK through a pathway that is unique for receptor tyrosine kinases. Oncogene 1999. The tumour suppressor protein VHL targets hypoxiainducible factors for oxygen-dependent proteolysis. Richly H. Margolin K. Szczylik C.64:7099 ^ 109. Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). 25. Hegland DD. Proc Am Soc Clin Oncol 2005. Mol Cell Biol 2002. Shibuya M. Maxwell PH. Clin Cancer Res 2007. Mosenkis A. et al. Rosen M.18: 2221 ^ 30. Ratain M. et al. 26.aacrjournals. 28. et al. Cancer Res 2004. Pappas PJ. Sethi R. Talpaz M. Carter C. Cerveira JJ. O’Dwyer PJ. Hilger RA. StadlerWM.22:7004 ^ 14. Liu M. 23.23:193s. et al.399:271 ^ 5. Escudier B. 20. et al. Eisen T.296:2404 ^ 7. Nat Biotechnol 2000. Gordon MS. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. et al. et al. 21.19:843 ^ 50. VEGF activates protein kinase C-dependent. Song S. Bednarski M.23:380s. et al. but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Doanes AM. J Clin Oncol 2001 . et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.284:H92 ^ 100. et al. Flaherty KT. Science 2002. 24.13(2 Suppl) January 15. 27. Hood JD. J Clin Oncol 2005.
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