The Role of Avastin in the Management of Recurrent Glioblastoma

Sweet, Jennifer A.; Feinberg, Michelle; Sherman, Jonathan H.

doi:10.1016/j.nec.2012.02.001

Cited by 14 publications

(14 citation statements)

References 54 publications

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“…Although a great deal is known about the aberrant biology exhibited by GBM, applying therapies against these biologic processes is limited by the blood-brain barrier which restricts many systemically administered therapies from reaching the brain parenchyma, including anti-cancer monoclonal antibodies [ 7 - 12 ]. Based on the knowledge that GBM are highly vascular, and express high levels of the angiogenic mediator vascular endothelial growth factor (VEGF) there have been several clinical studies of systemically administered anti-VEGF monoclonal antibodies, but the results have been disappointing, with little effect on the survival from GBM [ 9 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma

et al. 2014

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The median survival of glioblastoma multiforme (GBM) approximately 1 yr. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice.AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin ® ), an antihuman vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and Western. Immunohistochemistry showed the bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density, and tumor volume and increased survival. Administration of AAVrh. 10BevMab 1 wk after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. This data supports the strategy of AAV-mediated CNS gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an antiangiogenesis monoclonal antibody.

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Section: Introductionmentioning

confidence: 99%

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma

et al. 2014

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“…Studies have shown that Bevacizumab treatment leads to significant radiographic responses. However, these responses were only temporary and the ability of Bevacizumab to prolong overall survival of GBM patients remains in question [18]. New therapies capable of seeking out delivering cytotoxic agents to both the primary and infiltrative tumor foci are needed to improve therapy for GBM.…”

Section: Glioblastomamentioning

confidence: 99%

Neural stem cell therapy for cancer

Bagó

Sheets

Hingtgen

2016

Methods

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Cancers of the brain remain one of the greatest medical challenges. Traditional surgery and chemoradiation therapy are unable to eradicate diffuse cancer cells and tumor recurrence is nearly inevitable. In contrast to traditional regenerative medicine applications, engineered neural stem cells (NSCs) are emerging as a promising new therapeutic strategy for cancer therapy. The tumor-homing properties allow NSCs to access both primary and invasive tumor foci, creating a novel delivery platform. NSCs engineered with a wide array of cytotoxic agents have been found to significantly reduce tumor volumes and markedly extend survival in preclinical models. With the recent launch of new clinical trials, the potential to successfully manage cancer in human patients with cytotoxic NSC therapy is moving closer to becoming a reality.

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“…In gliomas, there is evidence that p53 mutations significantly increase the mean vessel density of pilocytic astrocytomas, and affect important regulators of angiogenesis including thrombospondin-1, serpin E1, and MMP-9 (Gaiser et al, 2009). Given the utility of bevacizumab (Avastin, an inhibitor of VEGF-A) in the clinic to treat recurrent gliomas (Sweet et al, 2012), inhibitors of angiogenesis have become an attractive target in the neuro-oncology clinic (Butowski, 2011). …”

Section: Angiogenesismentioning

confidence: 99%

The Combination of Novel Targeted Molecular Agents and Radiation in the Treatment of Pediatric Gliomas

Dasgupta¹,

Haas‐Kogan²

2013

Front. Oncol.

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Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent, or refractory pediatric brain tumors, radiation therapy (XRT) is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in pediatric gliomas is being exploited with the use of specific targeted inhibitors. These agents are additionally being combined with XRT to increase the efficacy and duration of local control. In this review, we discuss novel agents targeting three different pathways in gliomas, and their potential combination with XRT. BRAF is a serine/threonine kinase in the RAS/RAF/MAPK kinase pathway, which is integral to cellular division, survival, and metabolism. Two-thirds of pilocytic astrocytomas, a low-grade pediatric glioma, contain a translocation within the BRAF gene called KIAA1549:BRAF that causes an overactivation of the MEK/MAPK signaling cascade. In vitro and in vivo data support the use of MEK or mammalian target of rapamycin (mTOR) inhibitors in low-grade gliomas expressing this translocation. Additionally, 15–20% of high-grade pediatric gliomas express BRAF V600E, an activating mutation of the BRAF gene. Pre-clinical in vivo and in vitro data in BRAF V600E gliomas demonstrate dramatic cooperation between XRT and small molecule inhibitors of BRAF V600E. Another major signaling cascade that plays a role in pediatric glioma pathogenesis is the PI3-kinase (PI3K)/mTOR pathway, known to be upregulated in the majority of high- and low-grade pediatric gliomas. Dual PI3K/mTOR inhibitors are in clinical trials for adult high-grade gliomas and are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis that render them refractory to treatment. An analog of thalidomide, CC-5103 increases the secretion of critical cytokines of the tumor microenvironment, including IL-2, IFN-γ, TNF-α, and IL-10, and is currently being evaluated in clinical trials for the treatment of recurrent or refractory pediatric central nervous system tumors. In summary, several targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. This review article summarizes the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. In many cases, parallels are drawn to molecular mechanisms and targeted inhibitors of adult gliomas. We additionally discuss the potential mechanisms underlying the efficacy of these agents.

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The Role of Avastin in the Management of Recurrent Glioblastoma

Cited by 14 publications

References 54 publications

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma

Neural stem cell therapy for cancer

The Combination of Novel Targeted Molecular Agents and Radiation in the Treatment of Pediatric Gliomas

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