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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
600. if not as a starting dose. such as RAF. Spectrum of sorafenib in isolated kinase assays Kinase assays c-RAF mVEGFR2. EGFR. extracellular signal-regulated kinase. Delivery of a mutant RAF gene. The macular-papular rash associated with sorafenib is not commonly observed with bevacizumab (a VEGF antibody). Eligibility was not restricted based on histologic subtype or number of prior therapies. 4 of 14 at 600 mg twice daily. such as rash. This trial used modified WHO response criteria to avoid randomizing patients with clinically significant reductions in tumor volume. it is difficult to verify this point. Clin Cancer Res 2007. epidermal growth factor receptor. endothelial cells. VEGFR3 WT BRAF. and then after 2 months of therapy with 400 mg. Sorafenib was evaluated in four phase 1 trials. have dissipated. investigating distinct schedules of administration: three with interrupted dosing and one with continuous administration (20). incapable of binding ATP. and pericytes. Most patients had clear cell RCC. 2). This last group of Fig. In that study. 36% had tumor regressions of at least 25% and 32% had regression or progression of <25%. the agent clearly affects the maintenance of tumor vasculature and angiogenesis (19). 400 mg twice daily was selected for further development. to tumor endothelium results in inhibition of angiogenesis and tumorassociated endothelial cell apoptosis. 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.aacrjournals. PKC. Considering all grades of toxic effects. diarrhea. Nonetheless. According to the modified WHO criteria used in the protocol. is beyond the scope of this review. Of the 202 RCC patients enrolled. Consideration of other cancers. Nonetheless. In vivo. and the median number of prior therapies was 2. MEK. This leads one to speculate that a unique target of sorafenib. V599E BRAF p38. inhibition of mitogen-stimulated RAF activity was observed in peripheral mononuclear cells. might mediate this effect. most patients experience a decline in toxic effects after the first 4 to 6 weeks of treatment. meeting criteria for a conventional objective response. it is difficult to determine the relative contribution of each sorafenib target to the antitumor activity. 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). PDGFR-h FLT-3. Other targets. sorafenib inhibits the proliferation of RCC cell lines. such as p38. (18) have developed a nanoparticle delivery system that specifically targets tumor endothelium. PDGF receptor-h. Therefore. and 800 mg. 2007 748s www. and 3 of 6 at 800 mg twice daily. Pruritus is exclusively present in the setting of rash. Sorafenib targets in tumor cells. the three toxic effects that were clearly treatment related were rash. none of the 15 treated at 400 mg twice daily. where BRAF harbors activating mutations and might serve a more definitive test of sorafenib RAF-inhibitory properties. 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. such as melanoma. Sorafenib is one of the few toxicities that emerges relatively late in the course of treatment. and fatigue. Dose-limiting toxicity was observed in 1 of 6 patients treated at 200 mg twice daily. 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. are relatively unique to sorafenib and could be implicated in any of the toxicities that are unique to this agent. Hood et al. Hypertension is class effect of essentially all VEGF-targeted therapies and is discussed in detail below. sunitinib. Although it still difficult to discern which of the targets of sorafenib might be mediating this effect. ERK. 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. when other toxicities.org . It should be noted that in vitro. At doses of 200 mg twice daily and higher. and other small-molecule inhibitors of VEGFR and PDGF receptor. This is associated with apoptosis of tumor cells and prolonged regression of primary and metastatic tumors. 11% of patients had 50% regression by WHO criteria. 1. MEK. an experimental system that is independent of angiogenesis. Pharmacokinetic data support the selection of this dose because exposure did not increase significantly between cohorts treated with 400. direct tumor cytotoxicity may be a component of the clinical efficacy observed in RCC. mitogenactivated protein kinase/extracellular signal-regulated kinase kinase. and hand-foot syndrome. 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. Clinical Data Phase 1 and toxicity. diarrhea. These data support the necessity of RAF activity in the VEGF-induced activation of endothelial cells. Although it is reasonable to infer that the 600 mg dose level was intolerable based on a 29% dose-limiting toxicity rate. it is possible that longterm therapy at 600 mg twice daily is feasible. Given that it has been the only RAF kinase inhibitor to be evaluated clinically. protein kinase C.Table 1. The clinical development of sorafenib is notable for the large randomized discontinuation phase 2 trial. PKC. Phase 2 and 3 trials. The most common moderate or severe toxic effects were rash. in which activity in RCC was first observed (21). grade 3 events were infrequent. c-KIT EGFR.13(2 Suppl) January 15. hand-foot syndrome.
The significant difference in PFS (median. 46. Progression-free survival Kaplan-Meier analysis in Phase III renal cell carcinoma trial. 4. This will happen in the context in the E2804 (to be discussed later). We have observed that serum VEGF levels increase during the initial weeks of therapy with sorafenib. Correlative studies. In the setting of VEGF inhibition. This technique takes advantage of the influence of VEGF on vascular permeability and has been validated in preclinical models.0087) confirmed that disease stabilization was attributable to sorafenib. reduction in K tr significantly correlated with prolonged time-toprogression (P = 0.01) but not with the amount of tumor regression by computed tomography (P = 0. An interim analysis for overall survival revealed a nonsignificant trend toward improved survival (hazard ratio. Given that some tumors develop macroscopic evidence of necrosis. 24 versus 6 weeks. Of note. Although these patients continue to be followed up for overall survival. Of course. 95% confidence interval. This will undoubtedly limit the statistical power to detect a survival advantage for sorafenib. The antiangiogenic activity of sorafenib in vivo has been investigated in the context of the large phase 2 trial of sorafenib. 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. 0.aacrjournals. relatively large tumors are needed (>3 cm in some cases) to obtain robust measurements of K tr. any CTC grade.Sorafenib in RCC Fig. the objective response rate does not adequately summarize the effect of sorafenib on the natural history of metastatic RCC. Frequency of symptomatic toxicities in Phase III renal cell carcinoma trial (black bar. Although this study was designed to compare overall survival. Clearly. We conducted a pilot study using dynamic contrast-enhanced magnetic resonance imaging as a method of detecting changes in tumor vascular permeability (K tr.6%). The comparison of progression-free survival (PFS) in this cohort was the primary end point of the study. Previous studies in patients with other tumor types have correlated elevated K tr with high microvessel density and serum VEGF levels. in part. 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.018). Gadolinium diffuses across tumor vasculature more readily than normal vessels. gadolinium diffusion into tumors is reduced.5 versus 2. and the trial was terminated prematurely with placebo-treated patients crossed over to sorafenib (22). This is. Therefore. 40 weeks). 48% of the patients initially assigned to placebo crossed over to sorafenib soon after the PFS analysis. those who had a doubling or more in serum VEGF had a more Fig. This can be quantified by comparing the area under the time-enhancement curves before and during treatment. ref. 23). it is possible that K tr is detecting this type of effect and that changes in tumor size are somewhat independent. P < 0. Among a cohort of 20 patients treated with sorafenib. this trial established clinical activity in most patients. Taken together with the patients with tumor regression (median PFS. www. we did baseline dynamic contrast-enhanced magnetic resonance imaging and a followup assessment after several weeks of therapy. in the context of sorafenib therapy. each of these variables was treated as continuous. In addition. The investigator-assessed objective response rate was 10% by Response Evaluation Criteria in Solid Tumors criteria.00001) for sorafenib was nearly identical to that observed in the phase 2 trial (Fig. 3. grade 3). the first interim analysis for PFS was revealed to the investigators.22). 3).72. identification of a serum marker of pharmacodynamic effect would be preferable. 2007 . patients must at least undergo imaging studies beyond those required for clinical staging.8 months. P = 0. and interpreting the results requires a significant amount of expertise. 2. this small pilot study will require validation in a larger trial. This seems to be a class phenomenon for the VEGF-targeted agents in this disease. elevated K tr at baseline was significantly correlated with time-to-progression (P = 0. Thus. P < 0. Among 17 patients with varied RCC histologic subtypes. This is not a tumorrelated phenomenon but rather a systemic response to VEGF blockade.13(2 Suppl) January 15. 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. grey bar. This cutpoint was chosen based on the equal distribution of patients above and below this value. Although dynamic contrast-enhanced magnetic resonance imaging can assess metastatic tumors in a variety of metastatic sites.0005 was required to yield a definitive benefit. As hypothesized. as it is seen even among people without cancer.3% decline. patients (n = 65) were randomized to continue sorafenib or cross over to placebo.1-74. P = 0. The median PFS (5. 60. Nine hundred three patients with clear cell RCC refractory to one prior therapy were enrolled. both adverse prognostic signs in RCC. K tr was significantly lower after sorafenib treatment (median.org 749s Clin Cancer Res 2007. Unexpectedly.02).
We observed a consistent elevation in blood pressure for the entire cohort (Fig.Fig. This is a class effect observed not only with VEGFR inhibitors but also with the VEGF monoclonal antibody. This is supported by the rapid normalization of blood pressure following interruption of sorafenib. sorafenib will be combined with bevacizumab and temsirolimus. Sorafenib in combination regimens. we conducted an investigation of the mechanism of sorafenib-induced hypertension in patients with metastatic RCC (24). Mammalian target of rapamycin. The armamentarium of targeted agents against these factors is limited. In that study. which is up-regulated by the loss of the von Hippel Lindau gene in RCC. Although we have observed that increases in VEGF correlate with clinical benefit. basic fibroblast growth factor. Sorafenib is sufficiently tolerable to be combined with other agents. Based on its toxicity profile and target spectrum. The currently available evidence suggests that VEGFR antagonism is being achieved. sorafenib is well suited to inclusion in combination regimens. favorable outcome than those with little or no change in VEGF (Fig. A thorough analysis of the relation between changes in blood pressure and outcome has not been reported. Although we could not measure it directly. We found no significant relationship between previously described mediators of blood pressure and magnitude of increase. In particular. Open Discussion Dr. Wyeth Pharmaceuticals. we are initiating a randomized phase 2 trial in the cooperative groups (E2804). PA) is another agent that seems to affect angiogenesis at a point that is different from sorafenib. The rationale behind this approach is founded on the observation that serum VEGF levels increase following administration of VEGFR inhibitors. may be evidence of greater degrees of tumor hypoxia. and interleukin 8 have all been implicated in tumor angiogenesis (26). the number of potential combination regimens multiplies. including sorafenib. In addition to bevacizumab. An even more convenient biomarker of sorafenib effect might be treatment-related hypertension. For that reason. 5.aacrjournals. A more thorough evaluation of the blood pressure as a potential marker of VEGF inhibition is warranted. Bevacizumab (Genentech. Clin Cancer Res 2007. which is manifested on computed tomography scans. temsirolimus (CCI-779. Greater increases in VEGF levels in the setting of VEGFR blockade may simply relate to higher drug exposure. 2007 750s www. the target of temsirolimus. However. the development of new areas of tumor necrosis within tumors. we suspect that sorafenib is inhibiting nitric oxide production in endothelial cells. This threshold was selected based on nearly even numbers of patients above and below this value. Changes in serum VEGF while on sorafenib correlate with PFS. One combination of particular interest is simultaneous blockade of VEGFRs with depletion of secreted VEGF. temsirolimus may complement the effects of sorafenib at the level of the endothelial cell. it remains possible that increased VEGF production eventually mediates resistance to therapy. As the number of targeted agents with relevance to RCC increases. 4. The contribution of these various targets to the activity of sorafenib in RCC is not known. 6). CA) has been shown previously to deplete serum VEGF to undetectable levels at doses of 3 mg/kg and higher (27). Angiogenesis is mediated by other factors in addition to VEGF and PDGF. 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. Assessment of vascular permeability (Ktr) by DCE-MRI correlated with PFS or sorafenib (N = 17). South San Francisco. triggering more VEGF production. Collegeville. epidermal growth factor. 5). The combination of sorafenib and bevacizumab is in the midst of phase 1 evaluation. which has been shown previously to be VEGF mediated (25).13(2 Suppl) January 15. This will be the focus of investigations in the next generation of clinical trials. regulates the expression of hypoxia-inducible factor 1-a (28). The spectrum of kinases inhibited by sorafenib goes far beyond VEGFRs and is unique compared with other agents in this class. The combination of sorafenib and temsirolimus is being evaluated in a phase 1 trial. transforming growth factors a and h. In addition. By down-regulating hypoxia-inducible factor 1-a in the tumor cell. it is hypothesized that targeting multiple angiogenic growth factors will yield even greater benefits in RCC.org . There are several potential explanations for this relationship. In an effort to evaluate the currently available agents as doublets in parallel. Conclusions Sorafenib has established efficacy in RCC and is well tolerated.
Figlin: How does that explain how these drugs work in this disease? Dr. Dr. Sosman: But the hand-foot syndrome is seen across the board with all the multitargeted tyrosine kinase inhibitors. but I’ve never seen any data that quantify the percentage of. Curr Eye Res 2001 . 10. from you and others. KarpanenT. Rohovsky SA. Kodama T. 5. et al. Oku H. Egeblad M.407:249 ^ 57. et al. Pfeifer-Ohlsson S. et al. Dr.4:E2 ^ 5. Alitalo K. and perhaps compartments that are more complex with both VEGF-dependent components as well as components dependent on other growth factors.103:159 ^ 65. Fong GH. Lokker NA. et al. Nature 2000. Dr. et al. et al. McDermott: You said that you do not believe rebound is happening with this drug. The fms-like tyrosine kinase.org 751s Clin Cancer Res 2007. Carmeliet P. It might be there.Sorafenib in RCC Fig. we do not use intermittent dosing. To what extent we can add to them and optimize the antiangiogenic effect remains to be seen. Role of the Flt-1receptor tyrosine kinase in regulating the assembly of vascular endothelium. bevacizumab or in any of the early drugs on VEGF trial? Dr. Atkins: Was there any correlation between rash or hand-foot syndrome and clinical benefit? Of the targets that this drug is hitting. Escobedo JA. Hirschi KK. Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression. Dr. et al. Flaherty: Yes. 4. tumor cells in the rim probably aren’t dependent on tumor vasculature entirely for delivery of blood and nutrients. this lack of normal tissue repair causes either ulcerations at pressure points in the mouth or on the hands and feet. George: There may be different compartments to the vasculature: compartments that are immature. Karkkainen MJ. Wouldn’t this lead to rebound growth of RCC when VEGF receptor inhibitors are stopped abruptly? Dr.18:5117 ^ 24. et al. a receptor for vascular endothelial growth factor. Makinen T. such as platelet-derived growth factor. and suppression of neointima following vascular injury. Nature1995. 2. 14.84:298 ^ 305. the VEGF levels are clearly up on therapy. References 1. VEGF-dependent compartments. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. George: These are not homogeneous masses. Kawamura H. J Clin Invest 1999.376:66 ^ 70. 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. Everyone believed 5 years ago that angiogenesis happened only in wound healing and after a myocardial infarction in adults. Minowa O.13(2 Suppl) January 15. but after the 2-week break. This is a small window of overdrive. 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 other potential explanation is that the fraction of VEGF-dependent neovessels is differentially present as you move through zones of the tumor. for example. Sukhatme: Is it true that the hypertension seen with this drug is actually less than what is seen with. Hemo I. Flaherty: Exactly. for example. we have all seen data. Hiratsuka S. Proc Natl Acad Sci U S A 1998. Dr. Flaherty: With SU11248. The rash may be a RAF-driven phenomenon because it is different from the epidermal growth factor receptor rash. Karkkainen MJ. Science 1992.61:1786 ^ 90.95:9349 ^ 54.aacrjournals. Brekken RA. Nat Cell Biol 2000. Flaherty: The rash didn’t correlate with progression-free survival. 3. Atkins: My hypothesis for hand-foot syndrome and mucositis is that those areas of the body are constantly undergoing subclinical trauma. et al. Lin Q. J Pharmacol Exp Ther 2001. Blaskovich MA. that when you block the VEGF receptor with tyrosine kinase inhibitors serum VEGF levels increase. RossantJ. De Vries C. These inhibitors are probably only working on a subset of the tumor vasculature. Golijanin D. 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. I do not believe so. 6. Circ Res 1999. et al. Kuno J. 6. 11. However. the more heterogeneous. Angiogenesis in cancer and other diseases. Flaherty: We’ve never compared bevacizumab and this drug in a rigorous way. Ueno H. Flt-1lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Stastny VA. 7. Hollenbach S. Cancer Res 2000. Dr. and over time. You have angiogenesis that is part of minor levels of trauma that occur every day. Mechanism of sorafenib-induced hypertension in patients with metastatic RCC. Overholser JP. Dr. Beck LH. Yu JC. Lymphatic endothelium: a new frontier of metastasis research. 13. Flaherty: One potential explanation is that the dependence of the rim on tumor vasculature to deliver nutrients and oxygen is different than the core. Gertsenstein M.298: 1172 ^ 78. et al. 9. Cancer Res 2001 . Keshet E. Development 1991. Holmgren L. So. migration. Delarue FL. Development 1998. With sorafenib.Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. you do not have the normal tissue repair. GlaserA. Jain RK. The bigger they get. what factors do you think are responsible for those side effects? Dr. 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. 113:749 ^ 54. Dr. Dr. Benjamin LE. Design of GFB-111. Dr. With these agents. they’re down again to baseline. 125:1591 ^ 8. 12. that’s seen with the other drugs as well. 2007 . Itin A. Plateletderived growth factor-BB: a survival factor for the retinal microvasculature during periods of metabolic compromise.23:93 ^ 7. but to a degree that is not clinically meaningful.255:989 ^ 91. a platelet-derived growth factor binding www. Benjamin LE. Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation. but that is not the case. 8. people who have blood pressure elevations over systolic of 150 mm Hg or some other significant threshold. That is why it is harder to make those comments. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.
aacrjournals. et al.22:7004 ^ 14. Mol Cell Biol 2002.molecule with antiangiogenic and anticancer activity against human tumors in mice. Tang L. Sethi R. Eisen T. 20. Flaherty KT. et al.19:843 ^ 50. 18.399:271 ^ 5. but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Chiang GG. VEGF activates protein kinase C-dependent. J Clin Oncol 2006. Szczylik C. Bergers G.23:193s. Hudson CC. 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). Pappas PJ. J Clin Oncol 2004. Wiesener MS. Mechanisms of hypertension associated with BAY 439006. 22. Hood JD. Nat Biotechnol 2000. Wilhelm SM. Takahashi T. Pharmacodynamic study of BAY 43-9006 in patients with metastatic renal cell carcinoma. et al. et al. 15.22:4501. 17.296:2404 ^ 7. 2007 752s www.111:1287 ^ 95. Doanes AM. Frausto R. 23. 18:1065 ^ 70. 26. 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. Ueno H. Biochem Biophys Res Commun 1999. Rosen M.255:545 ^ 8. et al. Hilger RA. Margolin K. Cerveira JJ. 21. Oncogene 1999. The tumour suppressor protein VHL targets hypoxiainducible factors for oxygen-dependent proteolysis. Strumberg D. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. Ratain M. Clin Cancer Res 2007.284:H92 ^ 100.23:380s. VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide.org .64:7099 ^ 109. Talpaz M. Mosenkis A. StadlerWM. et al. 16. et al. Carter C. 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]. Proc Am Soc Clin Oncol 2005. Meyer-Morse N. Cancer Res 2004. Gallagher M. et al. 25. Chang GW. Liu M. O’Dwyer PJ. et al. 19. Richly H. et al. Song S. Shibuya M. Breslin JW. Escudier B. Maxwell PH. Nature 1999. Flaherty KT. 23:965 ^ 72. J Clin Oncol 2001 . et al.13(2 Suppl) January 15. 28. Gordon MS. 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.18: 2221 ^ 30. J Clin Oncol 2005. Am J Physiol Heart Circ Physiol 2003.Veronese ML. Science 2002. Proc Am Soc Clin Oncol 2005. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. et al.VEGF stimulates MAPK through a pathway that is unique for receptor tyrosine kinases. J Clin Invest 2003. Hegland DD. Regulation of hypoxia-inducible factor 1a expression and function by the mammalian target of rapamycin. 27. Tumor regression by targeted gene delivery to the neovasculature. 24.24:1363 ^ 9. Bednarski M.
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