A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma

Pan, Edward; Yu, Daohai; Yue, Binglin; Potthast, Lisa; Chowdhary, Sajeel; Smith, Pamela S.; Chamberlain, Marc C.

doi:10.1007/s11060-012-0943-z

Cited by 76 publications

(36 citation statements)

References 23 publications

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“…As a pan-inhibitor of VEGFR, particularly VEGFR2, sunitinib represents an attractive treatment option as an antiangiogenic drug in the therapy of glioma. However, clinical trials using sunitinib (Neyns et al, 2011;Pan et al, 2012) and several molecularly targeted agents (e.g., cediranib, pazopanib, vandetanib) have been unsuccessful in GBM therapy (Batchelor et al, 2010;Iwamoto et al, 2010;Kreisl et al, 2012). This may be due in part to the limited delivery of these agents across the BBB (Minocha et al, 2012a,b;Wang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies have shown significant antitumor and antiangiogenic activity of sunitinib (Zhou et al, 2008;Zhou and Gallo, 2009). However, recent clinical trials have been disappointing (Neyns et al, 2011;Pan et al, 2012). One possibility for these conflicting results could be attributed to the lack of adequate drug delivery, mediated by the efflux transporters at the BBB.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Oberoi

Mittapalli

Elmquist

2013

J Pharmacol Exp Ther

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This study quantitatively assessed transport mechanisms that limit the brain distribution of sunitinib and investigated adjuvant strategies to improve its brain delivery for the treatment of glioblastoma multiforme (GBM). Sunitinib has not shown significant activity in GBM clinical trials, despite positive results seen in preclinical xenograft studies. We performed in vivo studies in transgenic Friend leukemia virus strain B mice: wild-type, Mdr1a/b(2/2), Bcrp1(2/2), and Mdr1a/b(2/2)Bcrp1(2/2) genotypes were examined. The brain-to-plasma area under the curve ratio after an oral dose (20 mg/kg) was similar to the steady-state tissue distribution coefficient, indicating linear distribution kinetics in mice over this concentration range. Furthermore, the distribution of sunitinib to the brain increased after administration of selective P-glycoprotein (P-gp) or breast cancer resistance protein (Bcrp) pharmacological inhibitors and a dual inhibitor, elacridar, comparable to that of the corresponding transgenic genotype. The brain-to-plasma ratio after coadministration of elacridar in wild-type mice was ∼12 compared with ∼17.3 in Mdr1a/b(2/2)Bcrp1(2/2) mice. Overall, these findings indicate that there is a cooperation at the blood-brain barrier (BBB) in restricting the brain penetration of sunitinib, and brain delivery can be enhanced by administration of a dual inhibitor. These data indicate that the presence of cooperative efflux transporters, P-gp and Bcrp, in an intact BBB can protect invasive glioma cells from chemotherapy. Thus, one may consider the use of transporter inhibition as a powerful adjuvant in the design of future clinical trials for the targeted delivery of sunitinib in GBM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Oberoi

Mittapalli

Elmquist

2013

J Pharmacol Exp Ther

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“…Small‐molecule tyrosine kinase inhibitors such as imatinib mesylate (which targets PDGFR‐α, PDGFR‐β, c‐kit, and c‐abl), sunitinib (which targets VEGFR1‐3, PDGFR‐α, PDGFR‐β, Kit, Fms‐like tyrosine kinase 3 [Flt‐3], and colony stimulating factor 1 receptor [CSF‐1R]), and bevacizumab (which targets VEGF‐A) have been proven successful in treating various other cancers . Most of these agents, however, have been tested with only limited success in GBM therapy . Other VEGFR/PDGFR inhibitors such as sorafenib, pazopanib, and vatalanib have shown no significant clinical benefit .…”

Section: Therapeutic Approaches and Outcomes To Datementioning

confidence: 99%

Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date

Bastien

McNeill

Fine

2014

Cancer

126

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During the last decade, extensive multiplatform genome-wide analysis has yielded a wealth of knowledge regarding the genetic and molecular makeup of glioblastoma multiforme (GBM). These profiling studies support the emerging view that GBM comprises a group of highly heterogeneous tumor types, each with its own distinct molecular and genetic signatures. This heterogeneity complicates the process of defining reliable intertumor/intratumor biological states, which will ultimately be needed for classifying tumors and for designing effective customized therapies that target resultant disease pathways. The increased understanding of the molecular pathogenesis of GBM has brought the hope and expectation that such knowledge will lead to better and more rational therapies directed toward specific molecular targets. To date, however, these expectations have largely been unrealized. This review discusses some of the principal genetic and epigenetic aberrations found in GBM that appear promising for targeted therapies now and in the near future, and it offers suggestions for future directions concerning the rather disappointing results of clinical trials to date. Cancer 2014;121:502-16.

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“…In 88% of all glioma genetic alterations affecting the receptor‐tyrosine kinases (RTKs)/RAS/phosphatidylinositide 3'‐OH kinase (PI3K) networks have been found . While sunitinib, a potent inhibitor of multiple RTKs, showed potent anti‐angiogenic and anti‐invasive effects in GBM cell lines, the results of these preclinical studies could not be translated into clinical success, suggesting, that targeting only one single aberrantly activated pathway is inefficient to overcome the dysregulated oncogenic signaling network. Likewise the mTOR inhibitor rapamycin, a downstream target of PI3K signaling, showed in several models growth inhibiting activity .…”

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confidence: 99%

RIST: A potent new combination therapy for glioblastoma

Nonnenmacher

Westhoff

Fulda

et al. 2014

Intl Journal of Cancer

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Glioblastoma is a highly aggressive, common brain tumor with poor prognosis. Therefore, this study examines a new therapeutic approach targeting oncogenic and survival pathways combined with common chemotherapeutics. The RIST (rapamycin, irinotecan, sunitinib, temozolomide) and the variant aRIST (alternative to rapamycin, GDC-0941) therapy delineate growth inhibiting effects in established glioblastoma cell lines and primary cultured patient material. These combinations significantly decreased cell numbers and viability compared to inhibitors and chemotherapeutics alone with aRIST being superior to RIST. Notably, RIST/aRIST appeared to be apoptogenic evoked by reduction of anti-apoptotic protein levels of XIAP and BCL-2, with concomitant up-regulation of pro-apoptotic protein levels of p53 and BAX. The treatment success of RIST therapy was confirmed in an orthotopic mouse model. This combination treatment revealed significantly prolonged survival time and drastically reduced the tumor burden by acting anti-proliferative and pro-apoptotic. Surprisingly, in vivo, aRIST only marginally extended survival time with tumor volumes comparable to controls. We found that aRIST down-regulates the microvessel density suggesting an insufficient distribution of chemotherapy. Further, alterations in different molecular modes of action in vivo than in vitro suggest, that in vivo RIST therapy may mimic the superior aRIST protocol's pro-apoptotic inhibition of pAKT in vitro. Of note, all substances were administered in therapeutically relevant low doses with no adverse side effects observed. We also provide evidence of the potential benefits of the RIST therapy in a clinical setting. Our data indicates RIST therapy as a novel treatment strategy for glioblastoma achieving significant anti-tumorigenic activity avoiding high-dose chemotherapy.Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a mean overall patient survival time of 12 months. 1 Despite intensive research into new treatment strategies, the overall survival rate has not improved substantially over the last two decades. The most recent major alteration to the standard therapeutic protocol, then consisting of surgery followed by radiotherapy, was the addition of temozolomide, an alkylating agent, which increased the mean survival time by approximately four months. 2

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A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma

Cited by 76 publications

References 23 publications

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date

RIST: A potent new combination therapy for glioblastoma

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