A Randomized Trial of Bevacizumab, an Anti–Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer
James C. Yang, M.D., Leah Haworth, B.S.N., Richard M. Sherry, M.D., Patrick Hwu, M.D., Douglas J. Schwartzentruber, M.D., Suzanne L. Topalian, M.D., Seth M. Steinberg, Ph.D., Helen X. Chen, M.D., and Steven A. Rosenberg, M.D., Ph.D.
Background Mutations in the tumor-suppressor gene VHL causeoversecretion of vascular endothelial growth factor by clear-cellrenal carcinomas. We conducted a clinical trial to evaluatebevacizumab, a neutralizing antibody against vascular endothelialgrowth factor, in patients with metastatic renal-cell carcinoma.
Methods A randomized, double-blind, phase 2 trial was conductedcomparing placebo with bevacizumab at doses of 3 and 10 mg perkilogram of body weight, given every two weeks; the time toprogression of disease and the response rate were primary endpoints. Crossover from placebo to antibody treatment was allowed,and survival was a secondary end point.
Results Minimal toxic effects were seen, with hypertension andasymptomatic proteinuria predominating. The trial was stoppedafter the interim analysis met the criteria for early stopping.With 116 patients randomly assigned to treatment groups (40to placebo, 37 to low-dose antibody, and 39 to high-dose antibody),there was a significant prolongation of the time to progressionof disease in the high-dose–antibody group as comparedwith the placebo group (hazard ratio, 2.55; P<0.001). Therewas a small difference, of borderline significance, betweenthe time to progression of disease in the low-dose–antibodygroup and that in the placebo group (hazard ratio, 1.26; P=0.053).The probability of being progression-free for patients givenhigh-dose antibody, low-dose–antibody, and placebo was64 percent, 39 percent, and 20 percent, respectively, at fourmonths and 30 percent, 14 percent, and 5 percent at eight months.At the last analysis, there were no significant differencesin overall survival between groups (P>0.20 for all comparisons).
Conclusions Bevacizumab can significantly prolong the time toprogression of disease in patients with metastatic renal-cellcancer.
Studies of the hereditary form of clear-cell renal carcinoma,which occurs in the von Hippel–Lindau syndrome, led tothe identification of the von Hippel–Lindau tumor suppressorgene (VHL). The gene is mutated both in hereditary renal-cellcarcinoma (where one mutation is a germ-line mutation) and inmost cases of sporadic clear-cell renal carcinoma (where bothalleles have acquired mutations or deletions).1,2 One consequenceof these mutations is the overproduction of vascular endothelialgrowth factor through a mechanism involving hypoxia-induciblefactor .3,4,5,6,7 In addition, both VHL-deficient mice and vascularendothelial growth factor–knockout mice die in utero fromdefective vasculogenesis.8,9 Thus, by its regulation of vascularendothelial growth factor, the von Hippel–Lindau proteinis tightly linked to angiogenesis. Vascular endothelial growthfactor stimulates the growth of endothelial cells and appearsto be a central factor in angiogenesis, particularly duringembryogenesis, ovulation, wound healing, and tumor growth.10
Studies of human tumor xenografts in immunodeficient mice showedthat neutralization of vascular endothelial growth factor inhibitedthe growth of a variety of model tumors.11,12 Presta and colleagues"humanized" the murine antibody used in these studies, A.4.6.1,by placing its complementarity-determining (antigen-binding)regions into a human IgG1 constant-region framework and modifyingfurther amino acid residues to optimize antigen binding.13 Inthe resulting product, bevacizumab (or rhMAb-VEGF), 7 percentof the amino acids are from the murine antibody. In phase 1testing, bevacizumab had a low toxicity profile in most patients,had a terminal elimination half-life of approximately 21 days,and did not induce antibodies to bevacizumab.14 The severe toxiceffects that occurred in the phase 1 trial were infrequent intratumoralbleeding (including fatal hemoptysis), pulmonary emboli, andperipheral venous thrombosis. We conducted a randomized, placebo-controlledphase 2 trial of bevacizumab in patients with advanced renal-cellcarcinoma.
Methods
Patients
Patients with histologically confirmed renal cancer of the clear-celltype, measurable metastatic disease, and documented progressionof disease were eligible for this study. Other requirementsincluded an Eastern Cooperative Oncology Group (ECOG) performancestatus of 2 or lower and previous therapy with interleukin-2(or contraindications to standard interleukin-2 therapy). Theexclusion criteria were a history of central nervous systeminvolvement, any other therapy or major surgery within the previousfour weeks, a history of intratumoral bleeding, a serum creatininelevel of more than 2 mg per deciliter (17 µmol per liter),a serum bilirubin level of more than 2 mg per deciliter (34µmol per liter), and ischemic vascular disease.
All patients gave written informed consent. This protocol wasapproved by the institutional review board of the National CancerInstitute (NCI). The study was sponsored by the Cancer TherapyEvaluation program of the NCI, and bevacizumab was suppliedby Genentech under a cooperative research and development agreementwith the NCI. Trial design, data accrual (with the exceptionof assays for vascular endothelial growth factor and bevacizumabperformed by Genentech on coded patient specimens), data analysis,and manuscript preparation were performed entirely by the authors.
The patients were evaluated by physical examination, magneticresonance imaging of the brain, and complete computed tomographicscanning no more than one month before randomization, five weeksafter the beginning of therapy, and then every two months forthe first year of therapy and every three months for the secondyear of therapy.
A complete response was defined as the absence of all evidenceof disease for at least a month. A partial response was definedas a decrease of at least 50 percent in the sum of the productsof the maximal perpendicular diameters of measured lesions,lasting for a minimum of one month, with no progression of anylesion or appearance of new lesions. Minor and mixed responseswere not included as responses.
Annual interim evaluations were performed by an independentdata safety and monitoring board, and the method of O'Brienand Fleming was used to determine the threshold for statisticalsignificance at each interim evaluation that would constitutegrounds to recommend termination of the trial.15 For the firstyear of the trial, this threshold was a P value of 0.0006 orless; for the second year, it was a P value of 0.015 or less;and for the third year, it was a P value of 0.047 or less. Theestimated and actual accrual rates were similar enough thatthese proposed intervals did not require revision.
Randomization and Treatment
In this phase 2 study, the patients were stratified accordingto whether or not they had received interleukin-2 therapy andwere then randomly assigned to receive either a vehicle-onlyplacebo, 3 mg of bevacizumab per kilogram of body weight, or10 mg of bevacizumab per kilogram. During all treatment andevaluations, neither the patients nor any participating healthcare personnel were aware of the treatment assignment. Basedon pharmacokinetic modeling, treatment with bevacizumab beganwith one loading dose, in which 150 percent of the assigneddose was administered by intravenous infusion over a 2-hourperiod, and then, beginning one week later, the standard assigneddose was administered (by progressively shorter infusions thatreached a minimum of 30 minutes) every two weeks. Plasma levelsof vascular endothelial growth factor and serum levels of bevacizumabwere measured. The plasma vascular endothelial growth factorassay used the 3.5.F.8 murine antibody for both capture anddetection. This assay detects both free and bevacizumab-boundvascular endothelial growth factor equally, with a lower limitof detection of 40 pg per milliliter.
Evaluation
For the purposes of end-point evaluation, the criteria for declaringtumor progression were the unequivocal appearance of new lesions;an increase of more than 25 percent in the product of the maximalperpendicular diameters of any measured lesion, as comparedwith base-line evaluation (or the smallest size subsequent tobase line); or a tumor-related deterioration in ECOG performancestatus to 3 or more. For a declaration of progressive diseaseto be made, the lesions had to attain a minimal diameter of1.5 cm (to ensure accurate measurement).
The indications for removing patients from the study and unblindingtheir treatment assignments were as follows. To permit adequatetime for the initial assessment of the therapy while protectingpatients with rapid disease progression who were assigned toplacebo, the evaluation conducted five weeks after enrollmentdiffered from subsequent evaluations. At five weeks, patientswith increases of more than 2 cm in any lesion, a clinicallysignificant deterioration in performance status, or new, severesymptoms (e.g., bone pain or nerve compression) were removedfrom the study. At all other evaluations, the indication forremoval from the study was progressive disease. These differentindications for removal from the study did not affect the end-pointanalyses, which were always based on tumor progression, as definedabove.
Statistical Analysis
Using NCI Surgery Branch historical data from patients withno response to interleukin-2 therapy, we used the followingcriteria to estimate the sample size necessary to detect a doublingof the time to progression in patients receiving either doseof bevacizumab as compared with those receiving placebo: a 24-monthaccrual period, a 12-month evaluation period after the completionof accrual, a power of 80 percent, and an overall alpha of 0.05to detect a doubling of the hazard ratio for each of the twoprimary comparisons (high-dose antibody vs. placebo and low-doseantibody vs. placebo). The calculation indicated that 40 patientsper group would be required (50 were permitted, to allow forsome patients who could not be evaluated).
The primary evaluation was based on the time from enrollmentto disease progression; a secondary analysis examined the timeto disease progression from the five-week assessment, in orderto determine whether the effect of treatment was delayed andto ensure that small variations in the interval from the pretreatmentevaluation to the time of randomization did not affect the uniformdetermination of the time to progression. Each P value was adjustedfor the performance of two primary comparisons on the basisof treatment groups.
The time to progression and the overall response rate were theprimary end points, and the analyses were performed on an intention-to-treatbasis. Survival was declared a secondary end point, becausepatients whose disease progressed while they were receivingplacebo were offered crossover either to 3 mg of bevacizumabper kilogram alone or to a combination of 3 mg of bevacizumabper kilogram and thalidomide. The time to progression of diseaseand survival were assessed with use of Kaplan–Meier curvesand tested for significance by the log-rank test. Hazard ratioswere determined with the Cox proportional-hazards model. AllP values are two-tailed.
Results
Between October 1998 and September 2001, 116 patients were enrolled,of whom 108 had progressive disease during the course of thestudy. The median follow-up time from study entry was 27 months.Forty patients were randomly assigned to placebo, 37 to low-dosebevacizumab, and 39 to high-dose bevacizumab. All planned dosesof the study drug were given unless grade 3 toxic effects occurred,in which case doses were withheld as specified by the studyprotocol. Only one patient (who was assigned to low-dose bevacizumab)was lost to follow-up after therapy. The three groups had similardemographic and clinical characteristics and laboratory results(Table 1). All patients received at least one dose of the assigneddrug, and 114 of the 116 patients underwent at least one plannedfollow-up evaluation (evidence concerning disease progressionwas available for the remaining 2 patients).
Table 1. Characteristics of Patients before Treatment.
There were no life-threatening toxic effects (grade 4, majororgan) or deaths possibly related to bevacizumab (Table 2).Hypertension and asymptomatic proteinuria were associated withbevacizumab therapy (Table 2). Of 13 patients with grade 2 or3 hypertension, 7 (54 percent) had grade 2 or 3 proteinuria;of 63 patients with grade 0 or 1 hypertension, 10 (16 percent)had grade 2 or 3 proteinuria (P=0.007 by Fisher's exact test).None of these patients, or any other patient, had renal insufficiency.Hypertension and proteinuria uniformly decreased after the cessationof therapy, but death from renal cancer, the slow rate of correctionof hypertension and proteinuria, and the commencement of othertherapies prevented the documentation of complete resolutionof these toxic effects in all but one patient.
There were no episodes of grade 4 hypertension during randomizedtherapy, but in one patient who was initially assigned to placebo,hypertension with coma developed after the patient crossed overto low-dose bevacizumab plus thalidomide. These complicationsresolved completely after therapy was stopped. Typically, hypertensionduring the study was treated by the patients' private physicianswith standard regimens for essential hypertension. Among allbevacizumab-treated patients who required therapy for newlydiagnosed hypertension (for whom the dates of onset could bemost accurately determined), the median interval from the firstdose of bevacizumab to the onset of hypertension was 131 days(range, 7 to 316). Grade 1 or 2 hemoptysis developed in fourpatients (one receiving high-dose bevacizumab, one receivinglow-dose bevacizumab, and two receiving placebo), and one patientreceiving placebo had a pulmonary embolus.
At the second interim evaluation (which analyzed the data on110 patients), the NCI data safety and monitoring board recommendedclosure of accrual on the basis of the difference between theplacebo and high-dose bevacizumab groups in the time to progressionof disease. According to intention-to-treat analysis, progression-freesurvival in the group receiving 10 mg of bevacizumab per kilogram(with a median time to progression of 4.8 months) was significantlylonger than that in the placebo group (with a median time toprogression of 2.5 months, P<0.001 by the log-rank test)(Figure 1A). The difference between the time to progressionof disease in the group receiving 3 mg of bevacizumab per kilogram(median time, 3.0 months) and that in the placebo group wasof borderline significance (P=0.041 by the log-rank test) (Figure 1B).
Figure 1. Kaplan–Meier Analysis of Survival Free of Tumor Progression for Patients Receiving High-Dose Bevacizumab (Panel A) or Low-Dose Bevacizumab (Panel B), as Compared with Placebo.
The high dose of bevacizumab was 10 mg per kilogram of body weight. The low dose of bevacizumab was 3 mg per kilogram. Doses were given every two weeks. P values were calculated by the log-rank test.
The planned analysis of progression from the five-week assessmentyielded the same results. The percentages of patients assignedto high-dose bevacizumab, low-dose bevacizumab, and placebowho had no tumor progression were 64 percent, 39 percent, and20 percent, respectively, four months after randomization and30 percent, 14 percent, and 5 percent eight months after randomization.A Cox proportional-hazards model yielded hazard ratios for thetime to progression of disease of 2.55 among patients givenhigh-dose bevacizumab (P<0.001) and 1.26 among those givenlow-dose bevacizumab (P=0.053), as compared with those givenplacebo.
Only four patients had objective responses (all of which werepartial responses), and all of these had received high-dosebevacizumab; thus, the response rate for high-dose bevacizumabwas 10 percent (95 percent confidence interval, 2.9 to 24.2percent). One patient had a partial response for the maximaltreatment period of two years. This patient then stopped therapy,had a relapse six months later, and is currently having a secondpartial response after retreatment under a compassionate exemption(Figure 2). Another patient treated for two years had a sustainedminor response, had a relapse after stopping therapy, and hadanother minor response after being retreated.
Figure 2. Serial Radiographs of a Patient Treated with High-Dose Bevacizumab.
Panel A shows the pretreatment assessment (arrows indicate lymph-node metastases). Panel B shows a radiograph obtained two years later, when treatment was stopped during a partial response. Panel C shows relapse of tumor six months thereafter. Panel D shows a second partial response 3 months after therapy was restarted, which is ongoing at more than 18 months as of this writing.
Measurements of plasma vascular endothelial growth factor wereavailable for 113 patients. Of these, 76 had a base-line levelbelow the lower limit of detection (40 pg per milliliter). Therewere no significant associations between a detectable pretreatmentlevel of vascular endothelial growth factor and the clinicalresponse or the time to progression in either bevacizumab group(all P values were greater than 0.20). However, the limitedsensitivity of the assay does not permit the definitive conclusionthat there is no correlation between the base-line plasma levelof vascular endothelial growth factor and the clinical responseor the time to progression. After antibody therapy was started,the plasma levels of vascular endothelial growth factor rosesteadily (the assay measures both free and antibody-bound vascularendothelial growth factor). After 5 weeks and 13 weeks of therapy,all bevacizumab-treated patients had detectable plasma levelsof vascular endothelial growth factor. The median levels were196 and 246 pg per milliliter, respectively, for patients receivinghigh-dose bevacizumab and 155 and 170 pg per milliliter forpatients receiving low-dose bevacizumab. The percentages ofpatients assigned to placebo who had undetectable plasma levelsof vascular endothelial growth factor at base line, 5 weeks,and 13 weeks were 66 percent, 67 percent, and 75 percent, respectively.Patients receiving low-dose bevacizumab had mean (±SE)peak and trough serum levels of bevacizumab of 101±9and 39±3 µg per milliliter, respectively; patientsreceiving high-dose bevacizumab had mean peak and trough levelsof 392±24 and 157±13 µg per milliliter,respectively. In both groups, the trough levels were above thatneeded to abolish detectable free vascular endothelial growthfactor in the plasma of patients in previous phase 1 studies.14
At the most recent analysis, in February 2003, 19 of 116 patients(16 percent) were alive, and there were no significant differencesin survival between the treatment groups (all P values weregreater than 0.20) (Figure 3). The complete radiographic recordsof 113 patients (3 were no longer complete at the time of audit)were blindly audited by a team of extramural radiologists underthe supervision of the Cancer Therapy and Evaluation Programof the NCI. The prolongation of time to progression of diseasewas confirmed radiologically.
Figure 3. Overall Survival of Patients Receiving Placebo, Low-Dose Bevacizumab, or High-Dose Bevacizumab.
There were no significant differences among the treatment groups.
Discussion
We selected vascular endothelial growth factor as a target fortreatment of clear-cell kidney cancer because mutations in thevon Hippel–Lindau tumor-suppressor gene, which probablycause most sporadic clear-cell kidney cancers, result in overproductionof this growth factor by the tumors. In our study, the aim wasto neutralize vascular endothelial growth factor with a humanizedmonoclonal antibody (bevacizumab) in patients with metastaticclear-cell renal cancer. Using a randomized, double-blind, placebo-controlleddesign, we found that the time to tumor progression was prolongedby a factor of 2.55 in patients given 10 mg of bevacizumab perkilogram every two weeks, as compared with patients in the placebogroup. Survival was not a primary end point in this trial, whichallowed patients to cross over from placebo to bevacizumab therapyat the time of disease progression. Indeed, the survival ofbevacizumab-treated patients was not significantly differentfrom that of the patients receiving placebo.
During bevacizumab therapy, the plasma level of vascular endothelialgrowth factor rose. It is important to note that the assay weused measured both free and antibody-bound vascular endothelialgrowth factor. The explanation for this increase and its clinicalsignificance are unknown, but it might have been due to diminishedclearance of bevacizumab-bound, inactive vascular endothelialgrowth factor or to an antibody-mediated blockade of the bindingof vascular endothelial growth factor to its receptors.
Hypotheses about the mechanism responsible for the delay weobserved in tumor progression are based on in vitro data, theresults of treatment of human tumor xenografts in immunodeficientmice, and studies of human renal cancer. These data suggestthat the antitumor effects of the antibody against vascularendothelial growth factor are due to inhibition of angiogenesis.Both in vitro and in tumor xenografts, vascular endothelialgrowth factor has potent angiogenic activity, which is inhibitedby neutralizing antibodies to vascular endothelial growth factor;the result is a decrease in tumor blood flow and microvesseldensities.11 Human clear-cell renal cancers have significantlyhigher microvessel counts than non–clear-cell renal cancers,and these counts are correlated with the expression of vascularendothelial growth factor.16 Endothelial cells and hematopoieticcells (but not renal cancer cells) are the predominant cellsthat express receptors for vascular endothelial growth factor,but the inhibition of the growth of human tumor xenografts inimmunodeficient mice argues against contributions from an immunologicmechanism. For all these reasons, the inhibitory effect of bevacizumabon the growth of clear-cell renal cancer is likely to be dueto its antiangiogenic action.
Antiangiogenic strategies for the treatment of cancer have generatedwidespread enthusiasm based on promising in vitro and preclinicalstudies. The concepts that growing tumors require the manufactureof new blood vessels and that very little of the rest of thenormal adult body has such a requirement have led to the beliefthat there is valuable therapeutic potential in this area. Earlyclinical studies of antiangiogenic compounds such as endostatin,TNP-470, and thalidomide were not designed to assess their clinicalefficacy.17,18 In retrospect, only a randomized assessment ofa time-to-progression end point could have demonstrated theactivity of bevacizumab in renal cancer. Reliance on major responserates would have resulted in the conclusion that this drug wasineffective. Nevertheless, without a demonstration of improvedoverall survival, this single-agent trial serves primarily asa proof of principle and the basis for further investigation.
The magnitude of the clinical benefit of bevacizumab in thistrial was small. The differences in the time to the progressionof disease between the high-dose bevacizumab group and the placebogroup was only a few months. Nevertheless, the likelihood ishigh that this difference was due to true biologic activity.The lack of an overall survival benefit in this trial and thesmall size of the increase in the time to progression may reflectthe crossover design and the rigorous indications for declaringprogression and removing a patient from the study (an increasein diameter of any single lesion by as little as 12 percentcould constitute tumor progression). Some patients left thestudy with only small new lesions or mixed responses, but oftenwith minimal or no increase in the size of preexisting tumors.In fact, 23 patients treated with high-dose bevacizumab showedno net increase in the size of index lesions from base lineto the time of tumor progression. Tumor progression in thesepatients was typically based on the appearance of small newlesions or an increase in the size of some lesions that wasoffset by regression in other lesions. It would be worthwhileto determine survival in patients allowed to continue to receivebevacizumab despite tumor progression.
Future treatments for renal cancer that target angiogenic mechanismsshould consider pathways other than that mediated by vascularendothelial growth factor. There are other proteins in the localmicroenvironment of some tumors that can promote angiogenesis.For example, fibroblast growth factor 5, which has angiogenicactivity, is secreted by most renal cancers,19 suggesting thatcombinations of bevacizumab and inhibitors of members of thefibroblast growth factor family may have promise for treatmentof this disease. It is likely that the future of antiangiogenictherapy will require a rational combination of inhibitors, directedby a better understanding of the biology of each individualtype of cancer.
We are indebted to the Surgery Branch research nurses and immunotherapyfellows, the day hospital nursing staff, Don White, Maria Merino,W. Marston Linehan, Richard Klausner, Gwen Fyfe, and WilliamNovotny for their invaluable assistance in the conduct of thisstudy.
Source Information
From the Surgery Branch (J.C.Y., L.H., R.M.S., P.H., D.J.S., S.L.T., S.A.R.), the Biostatistics and Data Management Section (S.M.S.), and the Cancer Therapy Evaluation Program (H.X.C.), National Cancer Institute, Bethesda, Md.
Address reprint requests to Dr. Yang at Rm. 2B-37, Bldg. 10, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, or at james_yang{at}nih.gov.
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4: 1275-1283
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Shaikh, A., Wiisanen, M. E, Gunderson, H. D, Leung, N.
(2009). Acquired Fanconi Syndrome After Treatment with Capecitabine, Irinotecan, and Bevacizumab. The Annals of Pharmacotherapy
43: 1370-1373
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Yeh, E. T.H., Bickford, C. L.
(2009). Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.. J Am Coll Cardiol
53: 2231-2247
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Shord, S. S., Bressler, L. R., Tierney, L. A., Cuellar, S., George, A.
(2009). Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm
66: 999-1013
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Cantaert, T, De Rycke, L, Mavragani, C P, Wijbrandts, C A, Niewold, T B, Niers, T, Vandooren, B, Veys, E M, Richel, D, Tak, P P, Crow, M K, Baeten, D
(2009). Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade. Ann Rheum Dis
68: 1022-1029
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Baar, J., Silverman, P., Lyons, J., Fu, P., Abdul-Karim, F., Ziats, N., Wasman, J., Hartman, P., Jesberger, J., Dumadag, L., Hohler, E., Leeming, R., Shenk, R., Chen, H., McCrae, K., Dowlati, A., Remick, S. C., Overmoyer, B.
(2009). A Vasculature-Targeting Regimen of Preoperative Docetaxel with or without Bevacizumab for Locally Advanced Breast Cancer: Impact on Angiogenic Biomarkers. Clin. Cancer Res.
15: 3583-3590
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Lieb, W., Safa, R., Benjamin, E. J., Xanthakis, V., Yin, X., Sullivan, L. M., Larson, M. G., Smith, H. M., Vita, J. A., Mitchell, G. F., Sawyer, D. B., Vasan, R. S.
(2009). Vascular endothelial growth factor, its soluble receptor, and hepatocyte growth factor: clinical and genetic correlates and association with vascular function. Eur Heart J
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Izzedine, H., Ederhy, S., Goldwasser, F., Soria, J. C., Milano, G., Cohen, A., Khayat, D., Spano, J. P.
(2009). Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol
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Cortes, J., Saura, C., Atzori, F.
(2009). Risk of Venous Thromboembolism With Bevacizumab in Cancer Patients. JAMA
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Barros Costa, R. L.
(2009). Review Article: Targeted Therapy: Comprehensive Review. AM J HOSP PALLIAT CARE
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Feldman, D. R., Baum, M. S., Ginsberg, M. S., Hassoun, H., Flombaum, C. D., Velasco, S., Fischer, P., Ronnen, E., Ishill, N., Patil, S., Motzer, R. J.
(2009). Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma. JCO
27: 1432-1439
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Singhal, A. B., Kimberly, W. T., Schaefer, P. W., Hedley-Whyte, E. T.
(2009). Case 8-2009 -- A 36-Year-Old Woman with Headache, Hypertension, and Seizure 2 Weeks Post Partum. NEJM
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Gressett, S. M, Shah, S. R
(2009). Intricacies of Bevacizumab-Induced Toxicities and Their Management. The Annals of Pharmacotherapy
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Rodriguez, P. C., Ernstoff, M. S., Hernandez, C., Atkins, M., Zabaleta, J., Sierra, R., Ochoa, A. C.
(2009). Arginase I-Producing Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma Are a Subpopulation of Activated Granulocytes. Cancer Res.
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Hawfield, A., Freedman, B. I.
(2009). Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection. Ther Adv Cardiovasc Dis
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Neri, P, Salvolini, S, Mariotti, C, Mercanti, L, Celani, S, Giovannini, A
(2009). Long-term control of choroidal neovascularisation secondary to angioid streaks treated with intravitreal bevacizumab (Avastin). Br J Ophthalmol
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Golshayan, A. R., George, S., Heng, D. Y., Elson, P., Wood, L. S., Mekhail, T. M., Garcia, J. A., Aydin, H., Zhou, M., Bukowski, R. M., Rini, B. I.
(2009). Metastatic Sarcomatoid Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor-Targeted Therapy. JCO
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Birk, D. M., Barbato, J., Mureebe, L., Chaer, R. A.
(2009). Basic Science Review: Current Insights on the Biology and Clinical Aspects of VEGF Regulation. VASC ENDOVASCULAR SURG
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Zhang, J., Cao, R., Zhang, Y., Jia, T., Cao, Y., Wahlberg, E.
(2009). Differential roles of PDGFR-{alpha} and PDGFR-{beta} in angiogenesis and vessel stability. FASEB J.
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(2009). Molecular Pathways and Targeted Therapies for Renal Cell Carcinoma. Am Soc Clin Oncol Ed Book
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Johnson, B. M., Kamath, A. V., Leet, J. E., Liu, X., Bhide, R. S., Tejwani, R. W., Zhang, Y., Qian, L., Wei, D. D., Lombardo, L. J., Shu, Y.-Z.
(2008). Metabolism of 5-Isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737): Identification of an Unusual N-Acetylglucosamine Conjugate in the Cynomolgus Monkey. Drug Metab. Dispos.
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Dickler, M. N., Rugo, H. S., Eberle, C. A., Brogi, E., Caravelli, J. F., Panageas, K. S., Boyd, J., Yeh, B., Lake, D. E., Dang, C. T., Gilewski, T. A., Bromberg, J. F., Seidman, A. D., D'Andrea, G. M., Moasser, M. M., Melisko, M., Park, J. W., Dancey, J., Norton, L., Hudis, C. A.
(2008). A Phase II Trial of Erlotinib in Combination with Bevacizumab in Patients with Metastatic Breast Cancer. Clin. Cancer Res.
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Rini, B. I., Halabi, S., Rosenberg, J. E., Stadler, W. M., Vaena, D. A., Ou, S.-S., Archer, L., Atkins, J. N., Picus, J., Czaykowski, P., Dutcher, J., Small, E. J.
(2008). Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206. JCO
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Nalluri, S. R., Chu, D., Keresztes, R., Zhu, X., Wu, S.
(2008). Risk of Venous Thromboembolism With the Angiogenesis Inhibitor Bevacizumab in Cancer Patients: A Meta-analysis. JAMA
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Nowak, D. G., Woolard, J., Amin, E. M., Konopatskaya, O., Saleem, M. A., Churchill, A. J., Ladomery, M. R., Harper, S. J., Bates, D. O.
(2008). Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J. Cell Sci.
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Gupta-Abramson, V., Troxel, A. B., Nellore, A., Puttaswamy, K., Redlinger, M., Ransone, K., Mandel, S. J., Flaherty, K. T., Loevner, L. A., O'Dwyer, P. J., Brose, M. S.
(2008). Phase II Trial of Sorafenib in Advanced Thyroid Cancer. JCO
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Hahn, O. M., Yang, C., Medved, M., Karczmar, G., Kistner, E., Karrison, T., Manchen, E., Mitchell, M., Ratain, M. J., Stadler, W. M.
(2008). Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacodynamic Biomarker Study of Sorafenib in Metastatic Renal Carcinoma. JCO
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Schneider, B. P., Wang, M., Radovich, M., Sledge, G. W., Badve, S., Thor, A., Flockhart, D. A., Hancock, B., Davidson, N., Gralow, J., Dickler, M., Perez, E. A., Cobleigh, M., Shenkier, T., Edgerton, S., Miller, K. D.
(2008). Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100. JCO
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(2008). Out of the Shadows: CXC Chemokines in Promoting Aberrant Lung Cancer Angiogenesis. Cancer Prevention Research
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Stein, W. D., Yang, J., Bates, S. E., Fojo, T.
(2008). Bevacizumab Reduces the Growth Rate Constants of Renal Carcinomas: A Novel Algorithm Suggests Early Discontinuation of Bevacizumab Resulted in a Lack of Survival Advantage. The Oncologist
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Hutson, T. E., Figlin, R. A., Kuhn, J. G., Motzer, R. J.
(2008). Targeted Therapies for Metastatic Renal Cell Carcinoma: An Overview of Toxicity and Dosing Strategies. The Oncologist
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Eikesdal, H. P., Sugimoto, H., Birrane, G., Maeshima, Y., Cooke, V. G., Kieran, M., Kalluri, R.
(2008). Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity. Proc. Natl. Acad. Sci. USA
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Richmond, A., Su, Y.
(2008). Mouse xenograft models vs GEM models for human cancer therapeutics. DMM
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Azad, N. S., Posadas, E. M., Kwitkowski, V. E., Steinberg, S. M., Jain, L., Annunziata, C. M., Minasian, L., Sarosy, G., Kotz, H. L., Premkumar, A., Cao, L., McNally, D., Chow, C., Chen, H. X., Wright, J. J., Figg, W. D., Kohn, E. C.
(2008). Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity. JCO
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Dodd, L. E., Korn, E. L., Freidlin, B., Jaffe, C. C., Rubinstein, L. V., Dancey, J., Mooney, M. M.
(2008). Blinded Independent Central Review of Progression-Free Survival in Phase III Clinical Trials: Important Design Element or Unnecessary Expense?. JCO
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Carden, C. P., Larkin, J. M.G., Rosenthal, M. A.
(2008). What is the risk of intracranial bleeding during anti-VEGF therapy?. Neuro Oncol Duke
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Melichar, B., Koralewski, P., Ravaud, A., Pluzanska, A., Bracarda, S., Szczylik, C., Chevreau, C., Filipek, M., Delva, R., Sevin, E., Negrier, S., McKendrick, J., Santoro, A., Pisa, P., Escudier, B.
(2008). First-line bevacizumab combined with reduced dose interferon-{alpha}2a is active in patients with metastatic renal cell carcinoma. Ann Oncol
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Negrier, S.
(2008). Temsirolimus in metastatic renal cell carcinoma. Ann Oncol
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Hochster, H. S., Hart, L. L., Ramanathan, R. K., Childs, B. H., Hainsworth, J. D., Cohn, A. L., Wong, L., Fehrenbacher, L., Abubakr, Y., Saif, M. W., Schwartzberg, L., Hedrick, E.
(2008). Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study. JCO
26: 3523-3529
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Kulke, M. H., Lenz, H.-J., Meropol, N. J., Posey, J., Ryan, D. P., Picus, J., Bergsland, E., Stuart, K., Tye, L., Huang, X., Li, J. Z., Baum, C. M., Fuchs, C. S.
(2008). Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors. JCO
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Trotta, F., Apolone, G., Garattini, S., Tafuri, G.
(2008). Stopping a trial early in oncology: for patients or for industry?. Ann Oncol
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Champion, K. J., Guinea, M., Dammai, V., Hsu, T.
(2008). Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling. Cancer Res.
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Michaelson, M. D., Iliopoulos, O., McDermott, D. F., McGovern, F. J., Harisinghani, M. G., Oliva, E.
(2008). Case 17-2008 -- A 63-Year-Old Man with Metastatic Renal-Cell Carcinoma. NEJM
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Curwen, J. O., Musgrove, H. L., Kendrew, J., Richmond, G. H.P., Ogilvie, D. J., Wedge, S. R.
(2008). Inhibition of Vascular Endothelial Growth Factor-A Signaling Induces Hypertension: Examining the Effect of Cediranib (Recentin; AZD2171) Treatment on Blood Pressure in Rat and the Use of Concomitant Antihypertensive Therapy. Clin. Cancer Res.
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Kim, M., Liao, J., Dowling, M. L., Voong, K. R., Parker, S. E., Wang, S., El-Deiry, W. S., Kao, G. D.
(2008). TRAIL Inactivates the Mitotic Checkpoint and Potentiates Death Induced by Microtubule-Targeting Agents in Human Cancer Cells. Cancer Res.
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Mourad, J.-J., des Guetz, G., Debbabi, H., Levy, B. I.
(2008). Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol
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Frei, B. L., Soefje, S. A.
(2008). A Review of the Cardiovascular Effects of Oncology Agents. Journal of Pharmacy Practice
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Sun, D., Liu, W.-J., Guo, K., Rusche, J. J., Ebbinghaus, S., Gokhale, V., Hurley, L. H.
(2008). The proximal promoter region of the human vascular endothelial growth factor gene has a G-quadruplex structure that can be targeted by G-quadruplex-interactive agents. Molecular Cancer Therapeutics
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Benesch, M., Windelberg, M., Sauseng, W., Witt, V., Fleischhack, G., Lackner, H., Gadner, H., Bode, U., Urban, C.
(2008). Compassionate use of bevacizumab (Avastin(R)) in children and young adults with refractory or recurrent solid tumors. Ann Oncol
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Chintalapudi, M. R., Markiewicz, M., Kose, N., Dammai, V., Champion, K. J., Hoda, R. S., Trojanowska, M., Hsu, T.
(2008). Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells. Carcinogenesis
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Brostjan, C., Gebhardt, K., Gruenberger, B., Steinrueck, V., Zommer, H., Freudenthaler, H., Roka, S., Gruenberger, T.
(2008). Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels. Clin. Cancer Res.
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Waxman, J., Kenny, L., Ngan, S.
(2008). New treatments for kidney cancer. BMJ
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(2008). Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III. JCO
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Takei, Y., Saga, Y., Mizukami, H., Takayama, T., Ohwada, M., Ozawa, K., Suzuki, M.
(2008). Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice. Molecular Cancer Therapeutics
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Badgwell, B. D., Camp, E. R., Feig, B., Wolff, R. A., Eng, C., Ellis, L. M., Cormier, J. N.
(2008). Management of bevacizumab-associated bowel perforation: a case series and review of the literature. Ann Oncol
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Maharaj, A. S.R., Walshe, T. E., Saint-Geniez, M., Venkatesha, S., Maldonado, A. E., Himes, N. C., Matharu, K. S., Karumanchi, S. A., D'Amore, P. A.
(2008). VEGF and TGF-{beta} are required for the maintenance of the choroid plexus and ependyma. JEM
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Bender, J. L. G., Adamson, P. C., Reid, J. M., Xu, L., Baruchel, S., Shaked, Y., Kerbel, R. S., Cooney-Qualter, E. M., Stempak, D., Chen, H. X., Nelson, M. D., Krailo, M. D., Ingle, A. M., Blaney, S. M., Kandel, J. J., Yamashiro, D. J.
(2008). Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study. JCO
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Hiles, J. J., Kolesar, J. M.
(2008). Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma. Am J Health Syst Pharm
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Kadenhe-Chiweshe, A., Papa, J., McCrudden, K. W., Frischer, J., Bae, J.-O, Huang, J., Fisher, J., Lefkowitch, J. H., Feirt, N., Rudge, J., Holash, J., Yancopoulos, G. D., Kandel, J. J., Yamashiro, D. J.
(2008). Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation. Mol Cancer Res
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Claes, A., Wesseling, P., Jeuken, J., Maass, C., Heerschap, A., Leenders, W. P.J.
(2008). Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Molecular Cancer Therapeutics
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Ton, N.C., Parker, G.J.M., Jackson, A., Mullamitha, S., Buonaccorsi, G.A., Roberts, C., Watson, Y., Davies, K., Cheung, S., Hope, L., Power, F., Lawrance, J., Valle, J., Saunders, M., Felix, R., Soranson, J.A., Rolfe, L., Zinkewich-Peotti, K., Jayson, G.C.
(2007). Phase I Evaluation of CDP791, a PEGylated Di-Fab' Conjugate that Binds Vascular Endothelial Growth Factor Receptor 2. Clin. Cancer Res.
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Costa, L. J., Drabkin, H. A.
(2007). Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies. The Oncologist
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Cannistra, S. A., Matulonis, U. A., Penson, R. T., Hambleton, J., Dupont, J., Mackey, H., Douglas, J., Burger, R. A., Armstrong, D., Wenham, R., McGuire, W.
(2007). Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer. JCO
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Rudge, J. S., Holash, J., Hylton, D., Russell, M., Jiang, S., Leidich, R., Papadopoulos, N., Pyles, E. A., Torri, A., Wiegand, S. J., Thurston, G., Stahl, N., Yancopoulos, G. D.
(2007). Inaugural Article: VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc. Natl. Acad. Sci. USA
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Ebbinghaus, S., Hussain, M., Tannir, N., Gordon, M., Desai, A. A., Knight, R. A., Humerickhouse, R. A., Qian, J., Gordon, G. B., Figlin, R.
(2007). Phase 2 Study of ABT-510 in Patients with Previously Untreated Advanced Renal Cell Carcinoma. Clin. Cancer Res.
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Vredenburgh, J. J., Desjardins, A., Herndon, J. E. II, Marcello, J., Reardon, D. A., Quinn, J. A., Rich, J. N., Sathornsumetee, S., Gururangan, S., Sampson, J., Wagner, M., Bailey, L., Bigner, D. D., Friedman, A. H., Friedman, H. S.
(2007). Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme. JCO
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Harrison, M. L., Obermueller, E., Maisey, N. R., Hoare, S., Edmonds, K., Li, N. F., Chao, D., Hall, K., Lee, C., Timotheadou, E., Charles, K., Ahern, R., King, D. M., Eisen, T., Corringham, R., DeWitte, M., Balkwill, F., Gore, M.
(2007). Tumor Necrosis Factor {alpha} As a New Target for Renal Cell Carcinoma: Two Sequential Phase II Trials of Infliximab at Standard and High Dose. JCO
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Bukowski, R. M., Kabbinavar, F. F., Figlin, R. A., Flaherty, K., Srinivas, S., Vaishampayan, U., Drabkin, H. A., Dutcher, J., Ryba, S., Xia, Q., Scappaticci, F. A., McDermott, D.
(2007). Randomized Phase II Study of Erlotinib Combined With Bevacizumab Compared With Bevacizumab Alone in Metastatic Renal Cell Cancer. JCO
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Dass, C.R., Tran, T.M.N., Choong, P.F.M.
(2007). Angiogenesis Inhibitors and the Need for Anti-angiogenic Therapeutics. JDR
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Guse, K., Ranki, T., Ala-Opas, M., Bono, P., Sarkioja, M., Rajecki, M., Kanerva, A., Hakkarainen, T., Hemminki, A.
(2007). Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses. Molecular Cancer Therapeutics
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Morikawa, T., Sugiyama, A., Kume, H., Ota, S., Kashima, T., Tomita, K., Kitamura, T., Kodama, T., Fukayama, M., Aburatani, H.
(2007). Identification of Toll-Like Receptor 3 as a Potential Therapeutic Target in Clear Cell Renal Cell Carcinoma. Clin. Cancer Res.
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Li, Q., Yano, S., Ogino, H., Wang, W., Uehara, H., Nishioka, Y., Sone, S.
(2007). The Therapeutic Efficacy of Anti Vascular Endothelial Growth Factor Antibody, Bevacizumab, and Pemetrexed against Orthotopically Implanted Human Pleural Mesothelioma Cells in Severe Combined Immunodeficient Mice. Clin. Cancer Res.
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Beldner, M., Jacobson, M., Burges, G. E., Dewaay, D., Maize, J. C. Jr., Chaudhary, U. B.
(2007). Localized Palmar Plantar Epidermal Hyperplasia: A Previously Undefined Dermatologic Toxicity to Sorafenib. The Oncologist
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Advani, A., Kelly, D. J., Advani, S. L., Cox, A. J., Thai, K., Zhang, Y., White, K. E., Gow, R. M., Marshall, S. M., Steer, B. M., Marsden, P. A., Rakoczy, P. E., Gilbert, R. E.
(2007). Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. Proc. Natl. Acad. Sci. USA
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Haines, I. E.
(2007). A Positive Step Forward, but More Needed to Maximize Cost Benefits of New-Generation Cancer Therapies. JCO
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.3,4,5,6,7 In addition, both VHL-deficient mice and vascular endothelial growth factor–knockout mice die in utero from defective vasculogenesis.8,9 Thus, by its regulation of vascular endothelial growth factor, the von Hippel–Lindau protein is tightly linked to angiogenesis. Vascular endothelial growth factor stimulates the growth of endothelial cells and appears to be a central factor in angiogenesis, particularly during embryogenesis, ovulation, wound healing, and tumor growth.10 
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