pan-VEGF Receptor Tyrosine Kinase Inhibitor Research Articles

Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation. From 2471 compounds in a small molecular compound library composed of FDA-approved drugs, we found 77 candidates with a significant anti-inflammatory effect. In this study, we further characterized pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor (that was approved by the FDA for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma). We showed that pretreatment with pazopanib (1, 5, 10 μM) dose-dependently suppressed LPS-induced BV2 cell activation evidenced by inhibiting the transcription of proinflammatory factors iNOS, COX2, Il-1β, and Il-6 through the MEK4-JNK-AP-1 pathway. The conditioned medium from LPS-treated microglia caused mouse DA neuronal MES23.5 cell damage, which was greatly attenuated by pretreatment of the microglia with pazopanib. We established an LPS-stimulated mouse model by stereotactic injection of LPS into mouse substantia nigra. Administration of pazopanib (10 mg·kg-1·d-1, i.p., for 10 days) exerted significant anti-inflammatory and neuronal protective effects, and improved motor abilities impaired by LPS in the mice. Together, we discover a promising candidate compound for anti-neuroinflammation and provide a potential repositioning of pazopanib in the treatment of PD.

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model

Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib. Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment. After dosing of oral TMZ only, ECF-TMZ mean-C(max) and area under the concentration curve(AUC(0-∞)) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C(max) and AUC(0-∞) were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C(max) and AUC(0-∞), respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB "normalization" profile following cediranib treatment. In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.

Essential Role for Endocytosis in the Growth Factor-stimulated Activation of ERK1/2 in Endothelial Cells

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by binding to VEGF receptor 2 (VEGFR2) on endothelial cells (ECs). Downstream activation of the extracellular related kinases 1/2 (ERK1/2) is important for angiogenesis to proceed. Receptor internalization has been implicated in VEGFR2 signaling, but its role in the activation of ERK1/2 is unclear. To explore this question we utilized pitstop and dynasore, two small molecule inhibitors of endocytosis. First, we confirmed that both inhibitors block the internalization of VEGFR2 in ECs. We then stimulated ECs with VEGF in the presence and absence of the inhibitors and examined VEGFR2 signaling to ERK1/2. Activation of VEGFR2 and C-Raf still occurred in the presence of the inhibitors, whereas the activation of MEK1/2 and ERK1/2 was abrogated. Therefore, although internalization is not required for activation of either VEGFR2 or C-Raf in ECs stimulated with VEGF, internalization is necessary to activate the more distal kinases in the cascade. Importantly, inhibition of internalization also prevented activation of ERK1/2 when ECs were stimulated with other pro-angiogenic growth factors, namely fibroblast growth factor 2 and hepatocyte growth factor. In contrast, the same inhibitors did not block ERK1/2 activation in fibroblasts or cancer cells stimulated with growth factors. Finally, we show that these small molecule inhibitors of endocytosis block angiogenesis in vitro and in vivo. Therefore, receptor internalization may be a generic requirement for pro-angiogenic growth factors to activate ERK1/2 signaling in human ECs, and targeting receptor trafficking may present a therapeutic opportunity to block tumor angiogenesis.

Structure, Development, Preclinical and Clinical Efficacy of Tivozanib (KRN-951, AV-951)

Tivozanib hydrochloride monohydrate (tivozanib; formerly KRN-951, AV-951) is a potent pan-VEGF receptor tyrosine kinase inhibitor. The biological activity of tivozanib seems to outstand that of other VEGF tyrosine kinase inhibitors. In Phase I studies, observed side effects are generally mild, with hypertension being the most common adverse event. In single-agent Phase II and III studies in patients with advanced or metastatic renal cell carcinoma, tivozanib has demonstrated convincing clinical activity. Further clinical trials of tivozanib combined with various cytotoxic drug regimens as well as other classes of target-specific anticancer agents (e.g., mTOR inhibitors) for other indications are underway. Tivozanib has not yet been approved for regular use.

Increased Survival of Glioblastoma Patients Who Respond to Antiangiogenic Therapy with Elevated Blood Perfusion

The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.

Phase II Study of Cediranib in Patients with Malignant Pleural Mesothelioma: SWOG S0509

Malignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy. Patients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used. Fifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36%, and median progression-free survival was 2.6 months. Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape

Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular, and vascular parameters in autopsy tissues from 5 rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus 7 patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM, cellular density in the central area of the tumor was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemoradiation. Finally, cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy--characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology--without a second wave of angiogenesis.

Phase II Study of Cediranib, an Oral Pan–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma

Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.

A “Vascular Normalization Index” as Potential Mechanistic Biomarker to Predict Survival after a Single Dose of Cediranib in Recurrent Glioblastoma Patients

Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti-vascular endothelial growth factor (VEGF) therapy can "normalize" brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging-measured changes in vascular permeability/flow (i.e., K(trans)) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K(trans), microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P < 0.05). When we combined these three parameters into a "vascular normalization index," we found that it closely associated with overall survival (rho = 0.54; P = 0.004) and progression-free survival (rho = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials.

Phase Ib study of cediranib in combination with daily temozolomide and radiation in patients with newly diagnosed glioblastoma

e13010 Background: Pre-clinical evidence suggests antiangiogenic therapy combined with radiation therapy (RT) and chemotherapy may improve tumor control in patients with glioblastoma (GBM). We conducted a phase Ib study to evaluate the safety and maximum tolerated dose (MTD) of the combination of cediranib, a potent pan-VEGF receptor tyrosine kinase inhibitor, standard RT, and temozolomide (TMZ) in patients with newly diagnosed GBM who were not taking enzyme-inducing antiepileptic drugs (EIAED). Methods: After undergoing tumor biopsy or resection, six patients with pathologically confirmed GBM were treated with concurrent TMZ (75mg/m2/day), RT (60 Gy) and cediranib (dose level 1 = 20mg/day; dose level 2 = 30mg/day) followed by post-radiation TMZ (150–200 mg/m2 on days 1–5 of each 28 day cycle) and cediranib (45mg/day) for up to 6 monthly cycles. Cediranib was started concurrently with RT and TMZ 14–21 days after surgery. Results: Six patients were treated (cediranib 20mg = 3 patients; cediranib 30mg = 3 patients). No patients experienced a DLT, establishing the MTD for cediranib in combination with RT and TMZ as 30mg/day in this patient population. Expected toxicities of hypertension, fatigue, and palmar/plantar erythema were observed. During combined cediranib and TMZ therapy in the post-radiation setting, one patient discontinued cediranib because of toxicity (grade 3 transaminase elevation) and one patient required dose reduction to 15mg/day due to grade 3 proteinuria. No intratumoral or intracerebral hemorrhages were observed during the course of cediranib treatment. No cases of wound infection or wound dehiscence were observed. All patients are alive with a median follow-up of 156 days. Conclusions: Cediranib given in combination with standard RT and TMZ for newly diagnosed GBM patients not on EIAEDs is well tolerated and the MTD is 30mg/day. The phase II component of this trial is underway and will include correlative biomarker and MRI studies. [Table: see text]

Perfusion MR Imaging: Moving Forward

HomeRadiologyVol. 249, No. 2 PreviousNext Reviews and CommentaryEditorialsPerfusion MR Imaging: Moving ForwardA. Gregory SorensenA. Gregory SorensenAuthor Affiliations1From the Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 13th Street, Bldg 149, MC 2301, Boston, MA 02129. Received August 11, 2008; final version accepted August 13.Address correspondence to the author (e-mail: [email protected]).A. Gregory SorensenPublished Online:Nov 1 2008https://doi.org/10.1148/radiol.2492081429MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In References1 Villringer A, Rosen BR, Belliveau JW, et al. Dynamic imaging with lanthanide chelates in normal brain: contrast due to magnetic susceptibility effects. Magn Reson Med 1988;6:164–174. Crossref, Medline, Google Scholar2 Sorensen AG, Buonanno FS, Gonzalez RG, et al. Hyperacute stroke: evaluation with combined multisection diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology 1996;199:391–401. Link, Google Scholar3 Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007;38:1655–1711. Crossref, Medline, Google Scholar4 Wintermark M, Albers GW, Alexandrov AV, et al. Acute stroke imaging research roadmap. Stroke 2008;39:1621–1628. Crossref, Medline, Google Scholar5 Paulson ES, Schmainda KM. Comparison of dynamic susceptibility-weighted contrast-enhanced MR methods: recommendations for measuring relative cerebral blood volume in brain tumors. Radiology 2008;249:601–613. Google Scholar6 Boxerman J, Schmainda KM, Weisskoff RM. Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade whereas uncorrected maps do not. AJNR Am J Neuroradiol 2006;27:859–867. Medline, Google Scholar7 Cao Y, Tsien CI, Nagesh V, et al. Survival prediction in high-grade gliomas by MRI perfusion before and during early stage of RT [corrected]. Int J Radiat Oncol Biol Phys 2006;64:876–885. Crossref, Medline, Google Scholar8 Law M, Young RJ, Babb JS, et al. Gliomas: predicting time to progression or survival with cerebral blood volume measurements at dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology 2008;247:490–498. Link, Google Scholar9 Schmainda KM, Rand SD, Joseph AM, et al. Characterization of a first-pass gradient-echo spin-echo method to predict brain tumor grade and angiogenesis. AJNR Am J Neuroradiol 2004;25:1524–1532. Medline, Google Scholar10 Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83–95. Crossref, Medline, Google Scholar11 Hollingworth W, Medina LS, Lenkinski RE, et al. A systematic literature review of magnetic resonance spectroscopy for the characterization of brain tumors. AJNR Am J Neuroradiol 2006;27:1404–1411. Medline, Google ScholarArticle HistoryPublished in print: 2008 FiguresReferencesRelatedDetailsCited ByEuropean Journal of Radiology Open, Vol. 8Journal of Neuroimaging, Vol. 30, No. 2Der Radiologe, Vol. 56, No. 2Magnetic Resonance in Medical Sciences, Vol. 15, No. 2A Generic Support Vector Machine Model for Preoperative Glioma Survival AssociationsKyrre E. Emblem, Marco C. Pinho, Frank G. Zöllner, Paulina Due-Tonnessen, John K. Hald, Lothar R. Schad, Torstein R. Meling, Otto Rapalino, Atle Bjornerud, 8 December 2014 | Radiology, Vol. 275, No. 1Journal of Magnetic Resonance Imaging, Vol. 41, No. 2The Neuroradiology Journal, Vol. 28, No. 6Journal of Magnetic Resonance Imaging, Vol. 40, No. 1Neuro-Oncology, Vol. 16, No. suppl 7Pseudoprogression of Glioblastoma after Chemo- and Radiation Therapy: Diagnosis by Using Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging with Ferumoxytol versus Gadoteridol and Correlation with SurvivalSeymur Gahramanov, , Leslie L. Muldoon, , Csanad G. Varallyay, , Xin Li, , Dale F. Kraemer, , Rongwei Fu, , Bronwyn E. Hamilton, , William D. Rooney, , and Edward A. Neuwelt, 1 March 2013 | Radiology, Vol. 266, No. 3NMR in Biomedicine, Vol. 26, No. 8Neuroradiology, Vol. 55, No. 3Journal of Digital Imaging, Vol. 26, No. 2American Journal of Roentgenology, Vol. 200, No. 1American Journal of Neuroradiology, Vol. 33, No. 1International Journal of Radiation Oncology*Biology*Physics, Vol. 79, No. 2The Lancet Neurology, Vol. 9, No. 9American Journal of Neuroradiology, Vol. 31, No. 1Recommended Articles Imaging-based Selection for Endovascular Treatment in StrokeRadioGraphics2019Volume: 39Issue: 6pp. 1696-1713Whole-Brain CT Perfusion to Quantify Acute Ischemic Penumbra and CoreRadiology2016Volume: 279Issue: 3pp. 876-887Attenuation Changes in ASPECTS Regions: A Surrogate for CT Perfusion–based Ischemic Core in Acute Ischemic StrokeRadiology2019Volume: 291Issue: 2pp. 451-458Imaging of Heart Disease in WomenRadiology2016Volume: 282Issue: 1pp. 34-53Imaging Human Brain Perfusion with Inhaled Hyperpolarized 129Xe MR ImagingRadiology2017Volume: 286Issue: 2pp. 659-665See More RSNA Education Exhibits Brain CT Perfusion Studies: Turning False Ischaemic Penumbra into LightDigital Posters2019Stroke CT Perfusion Imaging: A Review of Quantitative and Qualitative ModalitiesDigital Posters2018Acute Ischemic Stroke: Time is Life — An Approach for No MistakesDigital Posters2019 RSNA Case Collection Acute ischemic strokeRSNA Case Collection2020Hypoxic ischemic encepholopathyRSNA Case Collection2020Herpes simplex encephalitisRSNA Case Collection2020 Vol. 249, No. 2 Metrics Altmetric Score PDF download

Characterization of blood vessels in brain autopsies of GBM patients who received antiangiogenic treatment

2009 Background: GBs have two types of vessels: co-opted and angiogenic. We hypothesize that antiangiogenic therapy normalizes angiogenic blood vessels and increases co-option of host vessels. However, to date the morphological changes in blood vessels of human tumors treated with antiangiogenic agents have not been studied. Methods: Interim results of a phase II clinical trial with a potent oral, pan-VEGF receptor tyrosine kinase inhibitor with activity against VEGF and PDGF receptors (Cediranib; AZD2171) showed a decrease in tumor contrast enhancement of more than 50% in 16/30 patients, decreased vessel permeability and vessel diameter - all hallmarks of vascular normalization. Autopsy specimens were obtained from 3 patients who were enrolled in this trial and received AZD2171 for 56, 120, and 140 days. All these patients had stable disease and none of these patients had radiographic progression at the time of AZD2171 termination. The interval between the last dose of AZD2171 and time of death ranged from 16 days to 3 months. Sections were stained for a series of markers relevant to microvessel integrity [CD31, CD71, MDR-1, nestin, CXCR4, SDF1a, PDGFRα,β] and analyses performed on two tumor areas and two corresponding contralateral areas free of bulk tumor for each patient. Results: Morphologically, the treated tumor vessels appeared more normal: endothelial hyperproliferation and glomeruloid-like vessels dramatically decreased and vessel density was restored close to that in the contralateral brain. PDGFRβ, which was expressed on all tumor vessels prior to treatment was nearly undetectable, and CD71 (a marker of the blood-brain-barrier) expression was partially restored. These changes were not seen in patients treated with temozolomide and radiation. Conclusions: Inhibition of VEGF and PDGF receptors led to significant changes in the tumor blood vessels. The vessel density increased while the endothelium morphology reverted to a more normal phenotype (monolayer), supporting the hypothesis that anti-VEGF therapy leads to vascular normalization and to vessel co-option. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Dyax, Pfizer Pharmaceutical, Takeda Pharmaceutical AstraZeneca

Abstract LB-247: A multidisciplinary phase II study of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma

Abstract Targeted agents are promising new therapeutics that have entered clinical trials for glioblastoma. AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients administered AZD2171 on a daily basis. Normalization has rapid onset, is reversible, and is associated with alleviation of brain edema (Batchelor TT, et al. Cancer Cell 2007;11:83-95). In this Phase II study of 31 recurrent glioblastoma subjects we now report clinical outcomes, including the proportion of patients alive and progression-free at 6 months (APF6) as the primary endpoint. Secondary endpoints include radiographic response proportion; progression-free survival; and overall survival and toxicity. At this time we are presenting radiographic response data, APF6, PFS, and OS on 31 patients. Thirty patients have experienced disease progression and one patient remains in follow-up without progression. The primary and secondary endpoints are tabulated below: Radiographic Responses Partial Response (more than 50% decrease in volume) in 16/30 (56%) APF6 [95% CI] 25.8% [14.7%, 46.9%] PFS [95% CI] 117 days [88, 145] OS [95% CI] 221 days [172, 285] Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities were observed in 9/16 patients with hypertension; fatigue and diarrhea were encountered most often. There have been no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in many of the patients enrolled. Blood biomarkers were serially assessed and it was observed that plasma VEGF, PlGF, and SDF1α were increased after treatment. Plasma PlGF and VEGF decreased upon cediranib discontinuation. Plasma bFGF and SDF1α and viable circulating endothelial cells increased when tumors escaped treatment with AZD2171. AZD2171 is a promising therapy for glioblastoma and an attractive therapeutic partner for chemotherapy or radiation.

Taming Glioblastoma: Targeting Angiogenesis

More than 30 years ago, Judah Folkman hypothesized that tumor angiogenesis could be a target of anticancer therapy. Some of the initial studies were actually performed in patients with glioblastomas, which had the greatest extent of tumor angiogenesis among a variety of human malignancies. The identification of vascular endothelial growth factor (VEGF) also provided a firm foundation for the development of antiangiogenic drugs. Fast forward to 2007: We now have multiple agents that specifically block tumor angiogenesis in various malignancies. In this issue of the Journal of Clinical Oncology, two groups independently describe phase II clinical trials of bevacizumab plus irinotecan for recurrent glioblastomas. Vredenburgh et al noted an objective response rate of 57% and a 6-month progression-free survival of 46% with this regimen. These results are remarkable indeed when compared with a benchmark response rate of 6% and 6-month progression-free survival of 15% from salvage cytotoxic chemotherapies. Although the radiographic responses were impressive, resolution of gadolinium enhancement could also be caused by bevacizumab-induced changes in vascular permeability, impairing our ability to visualize these tumors on magnetic resonance imaging (MRI). To demonstrate that bevacizumab plus irinotecan had an impact on the underlying tumor, Chen et al went one step further by using F-fluorothymidine positron emission tomography (FLT-PET) as an adjunctive measure of tumor response. They reported a 47% response rate by FLT-PET and a 65% 6-month survival, whereas metabolic responders lived three times longer than did nonresponders. These results are consistent with earlier findings that response to cytotoxic chemotherapies was associated with a significantly lower treatment failure rate and a hazard ratio of 0.5. Taken together, both studies establish a role for combining antiangiogenic drug and cytotoxic chemotherapy to treat recurrent glioblastomas. However, these results should be interpreted within the context of glioblastoma behaviors and our ability to measure treatment efficacy. The rationale for combining an antiangiogenic agent with cytotoxic chemotherapy is based on the phenomenon of vascular normalization, which leads to increased tissue oxygenation, decreased interstitial hypertension, and improved drug delivery to tumors. This was demonstrated experimentally with DTC101, a monoclonal antibody specific for VEGF receptor 2. As hyperpermeable vasculatures were pruned away by DTC101, increased tissue oxygenation acted synergistically with external-beam radiation in controlling U87 glioblastomas implanted in mouse brains. Interestingly, this normalization window peaked at day 5 of DTC101 treatment. For combination bevacizumab and cytotoxic chemotherapy, precise scheduling does not appear to be important, possibly because of immediate permeability changes and the prolonged half-life of bevacizumab. In patients treated with AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, Batchelor et al observed improvement in glioblastoma perfusion and permeability as measured by dynamic susceptibility contrast MRI within the first 24 hours. This is in contradiction to vascular damaging agents, which shut down well-developed tumor blood vessels and are highly schedule dependent when combined with cytotoxic chemotherapies. For example, ZD6126 induced hypoxia in U87 glioblastomas and interfered with radiation efficacy when administered 1hour before radiation, but it was synergistic with radiation when administered 24 hours after radiation. Similarly, 5,6-dimethyl-xanthenone-4 acetic acid and combretastatin A-4 disodium phosphate had the greatest tumor-cell kill when administered 1 to 3 hours after cisplatin. The current response criteria, or Macdonald’s criteria, may not be adequate for assessing glioblastoma response to antiangiogenic drugs. This is because tumor size is “estimated” on the basis of gadolinium leakage from hyperpermeable vasculatures. When antiangiogenic drugs change vascular permeability, they may alter the apparent size of glioblastomas on contrast-enhanced MRI or computed tomography, without affecting the underlying tumor mass. Therefore, it is critically important to incorporate adjunctive measures of tumor response, such as dynamic susceptibility contrast MRI for vascular perfusion and permeability and FLT or C-methylmethionine PET for tumor metabolism. Chen et al used FLT-PET and noted that metabolic response correlated with MRI response and patient survival. Unlike [F]fluorodeoxyglucose PET, FLT-PET has higher signal-to-noise ratio and is not confounded by a high rate of glucose utilization in the brain. But in order for FLT and C-methylmethionine PET to become accepted methods of assessing response in glioblastomas, more data are needed to evaluate their positive and negative predictive values. It is equally notable that not all patients responded to bevacizumab plus irinotecan. Heterogeneity in vascular response to bevacizumab may explain some of these failures. In the AZD2171 trial, some patients had worsening or unchanged perfusion and permeability, whereas others responded favorably. There may be secondary pathways for tumor angiogenesis to occur in nonresponders when either VEGF or the VEGF receptor is blocked. In Chen et al’s cohort, metabolic heterogeneity was also noted, as seen JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 30 OCTOBER 2

Normalization of Tumor Vasculature and Alleviation of Edema by AZD2171, A Pan-VEGF Receptor Tyrosine Kinase Inhibitor in Glioblastoma Patients

Normalization of Tumor Vasculature and Alleviation of Edema by AZD2171, A Pan-VEGF Receptor Tyrosine Kinase Inhibitor in Glioblastoma Patients

A phase II trial of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma

2001 Background: AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients treated with daily doses of AZD2171. Normalization has rapid onset, is reversible and is associated with alleviation of brain edema [Cancer Cell 2007; 11: 83]. Methods: In this phase II study of 30 recurrent glioblastoma subjects the primary endpoint was the proportion of patients alive and progression-free at 6 months (APF6). Secondary endpoints include radiographic response proportion; progression-free survival; overall survival and toxicity. At this time we are presenting radiographic response data and toxicity on the first 16 consecutive patients and APF6, PFS and OS on all 30 patients. Complete information will be available on all 30 patients at the time of presentation. Results: Twenty-eight patients have experienced disease progression and two patients remain in follow-up without progression. The primary and secondary endpoints are tabulated below: Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities of hypertension, fatigue and diarrhea were observed in 9/16 patients. There were no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in the first 16 patients enrolled. Blood biomarkers were serially assessed and elevated levels of bFGF, SDF1a and viable circulating endothelial cells correlated with disease progression. Conclusions: AZD2171 has activity in patients with recurrent glioblastoma. Combination studies of AZD2171 with radiation and chemotherapy are planned. [Table: see text] [Table: see text]

Tracking Normalization of Brain Tumor Vasculature by Magnetic Imaging and Proangiogenic Biomarkers

Clinical assessment of the response to antiangiogenic therapy has been cumbersome. A study in this issue of Cancer Cell demonstrates that a combination of magnetic resonance imaging (MRI) for quantification of normalized vessels with measurements of circulating levels of proangiogenic factors, including FGF2, SDF1, and viable circulating endothelial cells, provides an effective means to evaluate the response of recurrent glioblastoma to a prototypical pan-VEGF receptor tyrosine kinase inhibitor, AZD2171.

Blockade of Vascular Endothelial Growth Factor Signaling Ameliorates Diabetic Albuminuria in Mice

For investigation of how the vascular endothelial growth factor (VEGF) system participates in the pathogenesis of diabetic kidney disease, type 2 diabetic db/db and control db/m mice were treated intraperitoneally with vehicle or 2 mg/kg of a pan-VEGF receptor tyrosine kinase inhibitor, SU5416, twice a week for 8 wk. Efficacy of SU5416 treatment in the kidney was verified by the inhibition of VEGF receptor-1 phosphorylation. Glomerular VEGF immunostaining, normally increased in diabetes, was unaffected by SU5416. Plasma creatinine did not change with diabetes or SU5416 treatment. The primary end point of albuminuria increased approximately four-fold in the diabetic db/db mice but was significantly ameliorated by SU5416. Correlates of albuminuria were investigated. Diabetic glomerular basement membrane thickening was prevented in the SU5416-treated db/db mice, whereas mesangial matrix expansion remained unchanged by treatment. The density of open slit pores between podocyte foot processes was decreased in db/db diabetes but was partly increased toward normal by SU5416. Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416. Paradoxically, total nephrin protein by immunoblotting was increased in diabetes, pointing toward a possible dysregulation of nephrin trafficking. Diabetic albuminuria is partially a function of VEGF receptor signaling overactivity. VEGF signaling was found to affect a number of podocyte-driven manifestations such as GBM thickening, slit pore density, and nephrin quantity, all of which are associated with the extent of diabetic albuminuria. By impeding these pathophysiologic processes, VEGF receptor inhibition by SU5416 might become a useful adjunct to anti-albuminuria therapy in diabetic nephropathy.