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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
1. V599E BRAF p38. Delivery of a mutant RAF gene. are relatively unique to sorafenib and could be implicated in any of the toxicities that are unique to this agent. the three toxic effects that were clearly treatment related were rash. PDGFR-h FLT-3.Table 1. such as rash. Although it still difficult to discern which of the targets of sorafenib might be mediating this effect. 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. Most patients had clear cell RCC. Phase 2 and 3 trials. have dissipated. PKC. Spectrum of sorafenib in isolated kinase assays Kinase assays c-RAF mVEGFR2. Consideration of other cancers. (18) have developed a nanoparticle delivery system that specifically targets tumor endothelium. ERK. and the median number of prior therapies was 2. It should be noted that in vitro. 2007 748s www. At doses of 200 mg twice daily and higher. Other targets. 400 mg twice daily was selected for further development. In that study. MEK. such as RAF. is beyond the scope of this review. it is difficult to determine the relative contribution of each sorafenib target to the antitumor activity. Nonetheless. Hood et al. Dose-limiting toxicity was observed in 1 of 6 patients treated at 200 mg twice daily. Therefore. epidermal growth factor receptor. 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. investigating distinct schedules of administration: three with interrupted dosing and one with continuous administration (20). such as melanoma. Pharmacokinetic data support the selection of this dose because exposure did not increase significantly between cohorts treated with 400. and pericytes. 11% of patients had 50% regression by WHO criteria.org . In vivo. 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). mitogenactivated protein kinase/extracellular signal-regulated kinase kinase. Given that it has been the only RAF kinase inhibitor to be evaluated clinically. direct tumor cytotoxicity may be a component of the clinical efficacy observed in RCC. such as p38. if not as a starting dose. Sorafenib is one of the few toxicities that emerges relatively late in the course of treatment. diarrhea. 4 of 14 at 600 mg twice daily. and fatigue. when other toxicities. According to the modified WHO criteria used in the protocol. the agent clearly affects the maintenance of tumor vasculature and angiogenesis (19). The clinical development of sorafenib is notable for the large randomized discontinuation phase 2 trial. and hand-foot syndrome. sorafenib inhibits the proliferation of RCC cell lines. meeting criteria for a conventional objective response. 36% had tumor regressions of at least 25% and 32% had regression or progression of <25%. Considering all grades of toxic effects. This last group of Fig. 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. it is possible that longterm therapy at 600 mg twice daily is feasible. grade 3 events were infrequent. none of the 15 treated at 400 mg twice daily. 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. sunitinib. Although it is reasonable to infer that the 600 mg dose level was intolerable based on a 29% dose-limiting toxicity rate. 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. might mediate this effect. Sorafenib targets in tumor cells. This leads one to speculate that a unique target of sorafenib. This trial used modified WHO response criteria to avoid randomizing patients with clinically significant reductions in tumor volume. The macular-papular rash associated with sorafenib is not commonly observed with bevacizumab (a VEGF antibody). This is associated with apoptosis of tumor cells and prolonged regression of primary and metastatic tumors. Pruritus is exclusively present in the setting of rash. EGFR. to tumor endothelium results in inhibition of angiogenesis and tumorassociated endothelial cell apoptosis. c-KIT EGFR. extracellular signal-regulated kinase. most patients experience a decline in toxic effects after the first 4 to 6 weeks of treatment. PKC. Of the 202 RCC patients enrolled. Clin Cancer Res 2007. and 3 of 6 at 800 mg twice daily. These data support the necessity of RAF activity in the VEGF-induced activation of endothelial cells. inhibition of mitogen-stimulated RAF activity was observed in peripheral mononuclear cells. and other small-molecule inhibitors of VEGFR and PDGF receptor. VEGFR3 WT BRAF. and then after 2 months of therapy with 400 mg. where BRAF harbors activating mutations and might serve a more definitive test of sorafenib RAF-inhibitory properties. incapable of binding ATP. MEK. endothelial cells.13(2 Suppl) January 15. PDGF receptor-h. Clinical Data Phase 1 and toxicity. Nonetheless. 600. The most common moderate or severe toxic effects were rash. it is difficult to verify this point. in which activity in RCC was first observed (21). and 800 mg. Sorafenib was evaluated in four phase 1 trials. Hypertension is class effect of essentially all VEGF-targeted therapies and is discussed in detail below. diarrhea. an experimental system that is independent of angiogenesis. hand-foot syndrome. Eligibility was not restricted based on histologic subtype or number of prior therapies. 2). protein kinase C.
46. patients must at least undergo imaging studies beyond those required for clinical staging. Taken together with the patients with tumor regression (median PFS. both adverse prognostic signs in RCC. The significant difference in PFS (median. This technique takes advantage of the influence of VEGF on vascular permeability and has been validated in preclinical models. 24 versus 6 weeks. Frequency of symptomatic toxicities in Phase III renal cell carcinoma trial (black bar.1-74. as it is seen even among people without cancer. Previous studies in patients with other tumor types have correlated elevated K tr with high microvessel density and serum VEGF levels. The comparison of progression-free survival (PFS) in this cohort was the primary end point of the study. P = 0. In the setting of VEGF inhibition. 3. This cutpoint was chosen based on the equal distribution of patients above and below this value. this marker of otherwise poor prognosis seems to identify those most likely to receive clinical benefit. Clearly. We have observed that serum VEGF levels increase during the initial weeks of therapy with sorafenib. we did baseline dynamic contrast-enhanced magnetic resonance imaging and a followup assessment after several weeks of therapy. identification of a serum marker of pharmacodynamic effect would be preferable. Nine hundred three patients with clear cell RCC refractory to one prior therapy were enrolled. Although dynamic contrast-enhanced magnetic resonance imaging can assess metastatic tumors in a variety of metastatic sites. 2007 . this trial established clinical activity in most patients. The investigator-assessed objective response rate was 10% by Response Evaluation Criteria in Solid Tumors criteria.Sorafenib in RCC Fig.02). An interim analysis for overall survival revealed a nonsignificant trend toward improved survival (hazard ratio. 23). 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. 4. 40 weeks). K tr was significantly lower after sorafenib treatment (median. Given that some tumors develop macroscopic evidence of necrosis. 2. any CTC grade. elevated K tr at baseline was significantly correlated with time-to-progression (P = 0.0005 was required to yield a definitive benefit. 60. Correlative studies. the first interim analysis for PFS was revealed to the investigators. This is. those who had a doubling or more in serum VEGF had a more Fig.00001) for sorafenib was nearly identical to that observed in the phase 2 trial (Fig.22). P < 0.5 versus 2.3% decline. Although this study was designed to compare overall survival. 0.01) but not with the amount of tumor regression by computed tomography (P = 0. Thus. patients (n = 65) were randomized to continue sorafenib or cross over to placebo. gadolinium diffusion into tumors is reduced. it is possible that K tr is detecting this type of effect and that changes in tumor size are somewhat independent. This will happen in the context in the E2804 (to be discussed later).018). Of course. This will undoubtedly limit the statistical power to detect a survival advantage for sorafenib. 3).13(2 Suppl) January 15.0087) confirmed that disease stabilization was attributable to sorafenib. In addition. 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. relatively large tumors are needed (>3 cm in some cases) to obtain robust measurements of K tr. due to the related observation that many metastatic RCC lesions develop radiographically evident necrosis while on sorafenib therapy. the objective response rate does not adequately summarize the effect of sorafenib on the natural history of metastatic RCC. grade 3). The antiangiogenic activity of sorafenib in vivo has been investigated in the context of the large phase 2 trial of sorafenib. and the trial was terminated prematurely with placebo-treated patients crossed over to sorafenib (22).8 months. www.org 749s Clin Cancer Res 2007. 95% confidence interval. Progression-free survival Kaplan-Meier analysis in Phase III renal cell carcinoma trial. each of these variables was treated as continuous. As hypothesized. Among 17 patients with varied RCC histologic subtypes. This is not a tumorrelated phenomenon but rather a systemic response to VEGF blockade. and interpreting the results requires a significant amount of expertise. in part. Among a cohort of 20 patients treated with sorafenib. reduction in K tr significantly correlated with prolonged time-toprogression (P = 0. grey bar. Of note. 48% of the patients initially assigned to placebo crossed over to sorafenib soon after the PFS analysis.6%). in the context of sorafenib therapy. Unexpectedly. Although these patients continue to be followed up for overall survival. ref. P < 0. The median PFS (5. We conducted a pilot study using dynamic contrast-enhanced magnetic resonance imaging as a method of detecting changes in tumor vascular permeability (K tr.72. this small pilot study will require validation in a larger trial. This can be quantified by comparing the area under the time-enhancement curves before and during treatment. This seems to be a class phenomenon for the VEGF-targeted agents in this disease. P = 0. Therefore. Gadolinium diffuses across tumor vasculature more readily than normal vessels.aacrjournals.
We found no significant relationship between previously described mediators of blood pressure and magnitude of increase. This threshold was selected based on nearly even numbers of patients above and below this value. In addition to bevacizumab. it remains possible that increased VEGF production eventually mediates resistance to therapy. 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. which has been shown previously to be VEGF mediated (25). the target of temsirolimus. An even more convenient biomarker of sorafenib effect might be treatment-related hypertension. South San Francisco. Based on its toxicity profile and target spectrum. Bevacizumab (Genentech. One combination of particular interest is simultaneous blockade of VEGFRs with depletion of secreted VEGF. A thorough analysis of the relation between changes in blood pressure and outcome has not been reported. There are several potential explanations for this relationship. 2007 750s www. may be evidence of greater degrees of tumor hypoxia. 5. sorafenib will be combined with bevacizumab and temsirolimus. which is up-regulated by the loss of the von Hippel Lindau gene in RCC. Conclusions Sorafenib has established efficacy in RCC and is well tolerated. The rationale behind this approach is founded on the observation that serum VEGF levels increase following administration of VEGFR inhibitors. triggering more VEGF production. the number of potential combination regimens multiplies. the development of new areas of tumor necrosis within tumors. Assessment of vascular permeability (Ktr) by DCE-MRI correlated with PFS or sorafenib (N = 17). We observed a consistent elevation in blood pressure for the entire cohort (Fig. 4. which is manifested on computed tomography scans. and interleukin 8 have all been implicated in tumor angiogenesis (26). Greater increases in VEGF levels in the setting of VEGFR blockade may simply relate to higher drug exposure.aacrjournals. In an effort to evaluate the currently available agents as doublets in parallel. By down-regulating hypoxia-inducible factor 1-a in the tumor cell. regulates the expression of hypoxia-inducible factor 1-a (28). Sorafenib is sufficiently tolerable to be combined with other agents. Open Discussion Dr. The contribution of these various targets to the activity of sorafenib in RCC is not known. Wyeth Pharmaceuticals.org . Clin Cancer Res 2007. For that reason. it is hypothesized that targeting multiple angiogenic growth factors will yield even greater benefits in RCC. including sorafenib. CA) has been shown previously to deplete serum VEGF to undetectable levels at doses of 3 mg/kg and higher (27). The armamentarium of targeted agents against these factors is limited. This is supported by the rapid normalization of blood pressure following interruption of sorafenib. The currently available evidence suggests that VEGFR antagonism is being achieved.13(2 Suppl) January 15. 5). Sorafenib in combination regimens. Although we have observed that increases in VEGF correlate with clinical benefit. Mammalian target of rapamycin. favorable outcome than those with little or no change in VEGF (Fig. The combination of sorafenib and temsirolimus is being evaluated in a phase 1 trial. we conducted an investigation of the mechanism of sorafenib-induced hypertension in patients with metastatic RCC (24). A more thorough evaluation of the blood pressure as a potential marker of VEGF inhibition is warranted. basic fibroblast growth factor. temsirolimus may complement the effects of sorafenib at the level of the endothelial cell. Although we could not measure it directly. Collegeville. This is a class effect observed not only with VEGFR inhibitors but also with the VEGF monoclonal antibody. epidermal growth factor. The combination of sorafenib and bevacizumab is in the midst of phase 1 evaluation. temsirolimus (CCI-779.Fig. we are initiating a randomized phase 2 trial in the cooperative groups (E2804). However. Angiogenesis is mediated by other factors in addition to VEGF and PDGF. 6). In particular. As the number of targeted agents with relevance to RCC increases. PA) is another agent that seems to affect angiogenesis at a point that is different from sorafenib. sorafenib is well suited to inclusion in combination regimens. transforming growth factors a and h. In addition. Changes in serum VEGF while on sorafenib correlate with PFS. The spectrum of kinases inhibited by sorafenib goes far beyond VEGFRs and is unique compared with other agents in this class. This will be the focus of investigations in the next generation of clinical trials. we suspect that sorafenib is inhibiting nitric oxide production in endothelial cells. In that study.
you do not have the normal tissue repair. Karkkainen MJ.Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. I do not believe so. The other potential explanation is that the fraction of VEGF-dependent neovessels is differentially present as you move through zones of the tumor. Dr. De Vries C. people who have blood pressure elevations over systolic of 150 mm Hg or some other significant threshold. Development 1991. a receptor for vascular endothelial growth factor. Blaskovich MA. 7. we have all seen data. Nature1995. that when you block the VEGF receptor with tyrosine kinase inhibitors serum VEGF levels increase. for example. from you and others. To what extent we can add to them and optimize the antiangiogenic effect remains to be seen. Alitalo K. Sukhatme: Is it true that the hypertension seen with this drug is actually less than what is seen with. 14. Dr. Kawamura H. It might be there. 6. George: These are not homogeneous masses. Benjamin LE. Mechanism of sorafenib-induced hypertension in patients with metastatic RCC. tumor cells in the rim probably aren’t dependent on tumor vasculature entirely for delivery of blood and nutrients.aacrjournals. a platelet-derived growth factor binding www. Curr Eye Res 2001 . Dr. Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression. Lin Q. et al. Dr. but that is not the case. Hemo I. and suppression of neointima following vascular injury. 8. Escobedo JA. This is a small window of overdrive. These inhibitors are probably only working on a subset of the tumor vasculature. KarpanenT. Development 1998. et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. Delarue FL. et al.61:1786 ^ 90. Atkins: Was there any correlation between rash or hand-foot syndrome and clinical benefit? Of the targets that this drug is hitting. Overholser JP. 10. Role of the Flt-1receptor tyrosine kinase in regulating the assembly of vascular endothelium. that’s seen with the other drugs as well. That is why it is harder to make those comments.103:159 ^ 65.407:249 ^ 57. Flaherty: With SU11248. and over time. Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation. et al. George: There may be different compartments to the vasculature: compartments that are immature. Figlin: How does that explain how these drugs work in this disease? Dr. Carmeliet P. et al. Dr. Ueno H. 9.84:298 ^ 305. References 1.org 751s Clin Cancer Res 2007. However. for example. and perhaps compartments that are more complex with both VEGF-dependent components as well as components dependent on other growth factors. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Flaherty: We’ve never compared bevacizumab and this drug in a rigorous way.13(2 Suppl) January 15. what factors do you think are responsible for those side effects? Dr. J Pharmacol Exp Ther 2001. Lymphatic endothelium: a new frontier of metastasis research. 2. McDermott: You said that you do not believe rebound is happening with this drug. Cancer Res 2000. Wouldn’t this lead to rebound growth of RCC when VEGF receptor inhibitors are stopped abruptly? Dr. 3. Gertsenstein M. Kodama T. et al.298: 1172 ^ 78. 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. VEGF-dependent compartments. Dr.18:5117 ^ 24. bevacizumab or in any of the early drugs on VEGF trial? Dr. the more heterogeneous. but after the 2-week break. RossantJ. Pfeifer-Ohlsson S. Flaherty: Yes. Brekken RA. So. You have angiogenesis that is part of minor levels of trauma that occur every day. Benjamin LE. With these agents. Oku H. Holmgren L. but to a degree that is not clinically meaningful. Jain RK. Karkkainen MJ. Flt-1lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. J Clin Invest 1999. et al.255:989 ^ 91. Sosman: But the hand-foot syndrome is seen across the board with all the multitargeted tyrosine kinase inhibitors.4:E2 ^ 5. Rohovsky SA. the VEGF levels are clearly up on therapy. Angiogenesis in cancer and other diseases. The rash may be a RAF-driven phenomenon because it is different from the epidermal growth factor receptor rash. et al. 125:1591 ^ 8. Plateletderived growth factor-BB: a survival factor for the retinal microvasculature during periods of metabolic compromise. 12. Egeblad M. Minowa O. GlaserA. Lokker NA. Science 1992. 11. Proc Natl Acad Sci U S A 1998. Kuno J. migration. 113:749 ^ 54. Dr. Everyone believed 5 years ago that angiogenesis happened only in wound healing and after a myocardial infarction in adults. The fms-like tyrosine kinase. Design of GFB-111. 2007 . et al. The bigger they get. With sorafenib. we do not use intermittent dosing. 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. Cancer Res 2001 . Flaherty: The rash didn’t correlate with progression-free survival. Atkins: My hypothesis for hand-foot syndrome and mucositis is that those areas of the body are constantly undergoing subclinical trauma. Beck LH. this lack of normal tissue repair causes either ulcerations at pressure points in the mouth or on the hands and feet. Yu JC. Nat Cell Biol 2000. Hiratsuka S. et al.Sorafenib in RCC Fig. 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. Golijanin D. 4. Keshet E. 5. but I’ve never seen any data that quantify the percentage of. Hirschi KK. they’re down again to baseline. Fong GH. Flaherty: One potential explanation is that the dependence of the rim on tumor vasculature to deliver nutrients and oxygen is different than the core. Hollenbach S.95:9349 ^ 54. Stastny VA.376:66 ^ 70. Dr. Nature 2000. Dr. 6. 13.23:93 ^ 7. such as platelet-derived growth factor. Circ Res 1999. et al. Flaherty: Exactly. Makinen T. 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. Itin A. Dr.
et al. Ueno H.Veronese ML. Rosen M. J Clin Oncol 2001 . 28. Doanes AM. et al. Oncogene 1999. 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). 20.13(2 Suppl) January 15. et al. Szczylik C. VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. J Clin Invest 2003. Flaherty KT. J Clin Oncol 2005. Chiang GG. Mol Cell Biol 2002. et al. Talpaz M. Wilhelm SM. Pappas PJ. 2007 752s www. 21. Frausto R. Hood JD. Nature 1999.org .molecule with antiangiogenic and anticancer activity against human tumors in mice. Margolin K. 22. 18:1065 ^ 70. 16. Bergers G. 23:965 ^ 72.23:193s. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. Tang L.296:2404 ^ 7. et al. Cerveira JJ. Science 2002. J Clin Oncol 2004. Takahashi T. Pharmacodynamic study of BAY 43-9006 in patients with metastatic renal cell carcinoma. 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.399:271 ^ 5. 24.23:380s.22:4501. 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. Chang GW. et al. Am J Physiol Heart Circ Physiol 2003. 17. Cancer Res 2004. Hudson CC. 19. Sethi R. Tumor regression by targeted gene delivery to the neovasculature. 27.VEGF stimulates MAPK through a pathway that is unique for receptor tyrosine kinases. Mechanisms of hypertension associated with BAY 439006. 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. Flaherty KT. J Clin Oncol 2006. StadlerWM. The tumour suppressor protein VHL targets hypoxiainducible factors for oxygen-dependent proteolysis. Meyer-Morse N. Biochem Biophys Res Commun 1999. Nat Biotechnol 2000.284:H92 ^ 100.24:1363 ^ 9.18: 2221 ^ 30. Wiesener MS.19:843 ^ 50. Carter C. et al.255:545 ^ 8. et al. Hilger RA.64:7099 ^ 109.22:7004 ^ 14. 15. Eisen T. Regulation of hypoxia-inducible factor 1a expression and function by the mammalian target of rapamycin. Mosenkis A. Breslin JW. Hegland DD. Gordon MS. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. VEGF activates protein kinase C-dependent. et al. 23.aacrjournals. Song S. Richly H. O’Dwyer PJ. Shibuya M. et al. Escudier B.111:1287 ^ 95. 25. Liu M. Clin Cancer Res 2007. Proc Am Soc Clin Oncol 2005. et al. Bednarski M. et al. 18. Ratain M. et al. Gallagher M. but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Maxwell PH. Strumberg D.
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