Abstract:
BACKGROUND:The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development. METHODS:We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue. RESULTS:A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values. CONCLUSION:PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.
journal_name
Neuro Oncoljournal_title
Neuro-oncologyauthors
Butowski N,Colman H,De Groot JF,Omuro AM,Nayak L,Wen PY,Cloughesy TF,Marimuthu A,Haidar S,Perry A,Huse J,Phillips J,West BL,Nolop KB,Hsu HH,Ligon KL,Molinaro AM,Prados Mdoi
10.1093/neuonc/nov245subject
Has Abstractpub_date
2016-04-01 00:00:00pages
557-64issue
4eissn
1522-8517issn
1523-5866pii
nov245journal_volume
18pub_type
杂志文章,多中心研究相关文献
NEURO-ONCOLOGY文献大全abstract:BACKGROUND:RTOG 0625/ACRIN 6677 is a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma (GBM). This study investigated whether early posttreatment progression on FLAIR or postcontrast MRI assessed by central reading predicts overall survival (OS). METHODS:O...
journal_title:Neuro-oncology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1093/neuonc/not049
更新日期:2013-07-01 00:00:00
abstract::Grade II gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes - astrocytomas, oligodendrogliomas, and oligoastrocytomas - constitute true biological entities is largely unres...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1215/15228517-2007-041
更新日期:2008-02-01 00:00:00
abstract:Background:While recent genome-wide association studies have suggested novel low-grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived and re...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nox234
更新日期:2018-05-18 00:00:00
abstract:BACKGROUND:Promoter methylation of O(6)-methylguanine-DNA methyltransferase (MGMT) is an important predictive biomarker in glioblastoma. The T variant of the MGMT promoter-enhancer single nucleotide polymorphism (SNP; rs16906252) has been associated with the presence of MGMT promoter methylation in other cancers. We ex...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nov064
更新日期:2015-12-01 00:00:00
abstract:BACKGROUND:Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed. METHODS:Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treate...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/noaa083
更新日期:2020-11-26 00:00:00
abstract::To determine the effectiveness of stereotactic radiosurgery (SRS) treatment to central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL), we analyzed long-term results in VHL patients treated with SRS. Patients were enrolled in a prospective VHL natural history study, undergoing SRS treatment o...
journal_title:Neuro-oncology
pub_type: 临床试验,杂志文章
doi:10.1093/neuonc/nop018
更新日期:2010-01-01 00:00:00
abstract:Background:Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods:The relatio...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/now304
更新日期:2017-08-01 00:00:00
abstract::A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk ...
journal_title:Neuro-oncology
pub_type: 杂志文章,评审
doi:10.1093/neuonc/nov082
更新日期:2015-11-01 00:00:00
abstract::The purpose of this study was to evaluate the activity of single-agent bevacizumab in patients with recurrent anaplastic glioma and assess correlative advanced imaging parameters. Patients with recurrent anaplastic glioma were treated with bevacizumab 10 mg/kg every 2 weeks. Complete patient evaluations were repeated ...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nor091
更新日期:2011-10-01 00:00:00
abstract:Background:Glioblastoma cell-initiated vascularization is an alternative angiogenesis called vasculogenic mimicry. However, current knowledge on the mechanism of de novo vessel formation from glioblastoma stem cells (GSCs) is limited. Methods:Sixty-four glioblastoma samples from patients and 10 fluorescent glioma xeno...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nox016
更新日期:2017-08-01 00:00:00
abstract:BACKGROUND:We sought to determine the surgical treatment and functional outcome and identify the predictors of survival in a retrospective cohort of patients with spinal cord ependymoma using data collected from the Korea Spinal Oncology Research Group database. METHODS:The data regarding 88 patients who had been surg...
journal_title:Neuro-oncology
pub_type: 杂志文章,多中心研究
doi:10.1093/neuonc/not038
更新日期:2013-07-01 00:00:00
abstract::The homeobox transcription factor OTX2 plays an essential role during embryonic brain development. It is normally silenced in the adult brain, but is overexpressed by genomic amplification or other mechanisms in the majority of medulloblastomas (MBs). Retinoic acids (RAs) can suppress OTX2 expression and inhibit MB gr...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nop062
更新日期:2010-07-01 00:00:00
abstract::The REV3L gene, encoding the catalytic subunit of human polymerase zeta, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of certain tumors. However, the role of REV3L in regulating the sensitivity of glioma cells to chemotherapy remains unknown. In this study, we investigated the expres...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1215/15228517-2009-015
更新日期:2009-12-01 00:00:00
abstract::Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by...
journal_title:Neuro-oncology
pub_type: 杂志文章,评审
doi:10.1093/neuonc/now016
更新日期:2016-07-01 00:00:00
abstract:BACKGROUND:Brain metastases are generally considered to be well demarcated from the surrounding brain parenchyma, although infiltrative growth patterns have been observed. We systemically investigated infiltration patterns and expression of adhesion molecules in a large and well-defined series of autopsy cases of brain...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/not112
更新日期:2013-12-01 00:00:00
abstract:BACKGROUND:No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease. METHODS:We report the first population-based analysis on B...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nou099
更新日期:2015-01-01 00:00:00
abstract::Development of model systems that recapitulate the molecular heterogeneity observed among glioblastoma multiforme (GBM) tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maint...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1215/15228517-2008-113
更新日期:2009-10-01 00:00:00
abstract:Background:Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nox109
更新日期:2017-10-19 00:00:00
abstract:BACKGROUND:The standard of care for newly diagnosed glioblastoma is maximal safe surgical resection, followed by chemoradiation therapy. We assessed carmustine wafer implantation efficacy and safety when used in combination with standard care. METHODS:Included were adult patients with (n = 354, implantation group) and...
journal_title:Neuro-oncology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1093/neuonc/nov126
更新日期:2015-12-01 00:00:00
abstract::We explored the associations of aberrant DNA methylation patterns in 12 candidate genes with adult glioma subtype, patient survival, and gene expression of enhancer of zeste human homolog 2 (EZH2) and insulin-like growth factor-binding protein 2 (IGFBP2). We analyzed 154 primary glioma tumors (37 astrocytoma II and II...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/noq190
更新日期:2011-03-01 00:00:00
abstract::Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777...
journal_title:Neuro-oncology
pub_type: 杂志文章,多中心研究
doi:10.1215/15228517-2008-070
更新日期:2008-12-01 00:00:00
abstract::In photodynamic diagnosis, 5-aminolevulinic acid (5-ALA) is widely used for the fluorescence-guided resection of malignant brain tumors, where 5-ALA is converted to protoporphyrin IX, which exhibits strong fluorescence. Little is known, however, about the detailed molecular mechanisms underlying 5-ALA-induced fluoresc...
journal_title:Neuro-oncology
pub_type: 杂志文章,收录出版
doi:10.1093/neuonc/nor116
更新日期:2011-11-01 00:00:00
abstract::Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this ...
journal_title:Neuro-oncology
pub_type: 临床试验,杂志文章
doi:10.1215/S1152851703000353
更新日期:2005-01-01 00:00:00
abstract::Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular co...
journal_title:Neuro-oncology
pub_type: 杂志文章,评审
doi:10.1093/neuonc/nox183
更新日期:2018-04-09 00:00:00
abstract::Survivorship has become a significant topic within oncologic care. The tools and means by which the provision of survivorship care can be implemented and delivered are in development and are the focus of significant research oncology-wide. These tools and methods include innovations of survivorship care delivery, surv...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/noy110
更新日期:2018-11-09 00:00:00
abstract::Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in toxicity a...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1215/15228517-2008-089
更新日期:2009-06-01 00:00:00
abstract::We investigated the activation of platelet-derived growth factor (PDGF) receptor A (PDGFRA), PDGF receptor B (PDGFRB), epidermal growth factor receptor (EGFR), and their downstream pathways in malignant peripheral nerve sheath tumors (MPNSTs). PDGFRA, PDGFRB, and EGFR were immunohistochemically, biochemically, cytogen...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1215/15228517-2009-003
更新日期:2009-12-01 00:00:00
abstract::Background Nuclear factor IA (NFIA), a transcription factor and essential regulator in embryonic glial development, is highly expressed in human glioblastoma (GBM) compared with normal brain, but its contribution to GBM and cancer pathogenesis is unknown. Here we demonstrate a novel role for NFIA in promoting growth a...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/not167
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND:Malignant glioma is a common and lethal primary brain tumor in adults. Here we identified a novel oncoprotein, vesicle-associated membrane protein 8 (VAMP8), and investigated its roles in tumorigenisis and chemoresistance in glioma. METHODS:The expression of gene and protein were determined by quantitative P...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/nou219
更新日期:2015-03-01 00:00:00
abstract:Background:Glioblastoma (GBM) is one of the most common, aggressive, and invasive human brain tumors. There are few reliable mechanism-based therapeutic approaches for GBM patients. The transcriptional repressor RE1 silencing transcriptional factor (REST) regulates the oncogenic properties of a class of GBM stem-like c...
journal_title:Neuro-oncology
pub_type: 杂志文章
doi:10.1093/neuonc/now232
更新日期:2017-04-01 00:00:00