Abstract:
BACKGROUND:Anaplastic lymphoma kinase (ALK) is expressed in ~ 60% of glioblastomas and conveys tumorigenic functions. Therefore, ALK inhibitory strategies with alectinib are conceivable for patients with glioblastoma. The aims of this preclinical study were to investigate efficacy as well as to understand and potentially overcome primary and acquired resistance mechanisms of alectinib in glioblastoma. METHODS:Efficacy of alectinib was analyzed dependent on ALK expression in different glioblastoma initiating cells and after lentiviral knockdown of ALK. Alectinib resistant cells were generated by continuous treatment with increasing alectinib doses over 3 months. M-RNA, phospho-protein and protein regulation were analyzed to decipher relevant pathways associated to treatment or resistance and specifically inhibited to evaluate rational salvage therapies. RESULTS:Alectinib reduced clonogenicity and proliferation and induced apoptosis in ALK expressing glioblastoma initiating cells, whereas cells without ALK expression or after ALK depletion via knockdown showed primary resistance against alectinib. High expression of cMyc and activation of the ERK1/2 pathway conferred resistance against alectinib in ALK expressing glioblastoma cells. Pharmacological inhibition of these pathways by cMyc inhibitor or MEK inhibitor, trametinib, overcame alectinib resistance and re-sensitized resistant cells to continued alectinib treatment. The combination of alectinib with radiotherapy demonstrated synergistic effects in inhibition of clonogenicity in non-resistant and alectinib resistant glioblastoma cells. CONCLUSION:The data offer rationales for alectinib treatment in ALK expressing glioblastoma and for the use of ALK expression status as potential biomarker for alectinib treatment. In addition, the results propose MEK inhibition or radiotherapy as reasonable salvage treatments after acquired alectinib resistance.
journal_name
J Neurooncoljournal_title
Journal of neuro-oncologyauthors
Berberich A,Schmitt LM,Pusch S,Hielscher T,Rübmann P,Hucke N,Latzer P,Heßling B,Lemke D,Kessler T,Platten M,Wick Wdoi
10.1007/s11060-019-03348-zsubject
Has Abstractpub_date
2020-01-01 00:00:00pages
9-23issue
1eissn
0167-594Xissn
1573-7373pii
10.1007/s11060-019-03348-zjournal_volume
146pub_type
杂志文章abstract::The activation of autocrine loops involving proto-oncogene related receptor tyrosine kinases has led to the analysis of a large number of growth factor systems in human glioma specimens and cell lines. The ErbB-2 system, also called HER-2 or neu, is analogous to the epidermal growth factor receptor system (EGF-R, ErbB...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/a:1005837122181
更新日期:1997-12-01 00:00:00
abstract::Invasion of the meninges is a relatively common complication of head and neck rhabdomyosarcoma (RMS), while RMS arising primarily within the brain or meninges is rare. We report the case of an 11-year old child with a primary "primitive" frontal lobe tumor, subsequent leptomeningeal spread and fatal intratumoral hemor...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/BF02571302
更新日期:1987-01-01 00:00:00
abstract::Extensive surgical resection of centrally localized, newly diagnosed glioblastoma can lead to opening ventricles and therefore carries a potential risk of spreading tumor cells into the cebrospinal fluid. However, whether ventricle opening consequently implies a greater frequency of distant tumor recurrence after radi...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-016-2068-2
更新日期:2016-05-01 00:00:00
abstract::Differentiating oligodendroglioma from extraventricular neurocytoma by conventional light microscopy alone can present a diagnostic challenge. We report pathologic findings of an unusual spinal cord tumor from a 33-year-old male patient which showed hybrid features of oligodendroglioma and extraventricular neurocytoma...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-006-9268-0
更新日期:2007-04-01 00:00:00
abstract::During glioma resection, 5-aminolevulinic acid (5-ALA) and fluorescein sodium (Fl-Na) are used for photodynamic tumor visualization. The objective of this study was to evaluate the pathological findings of the boundary zone between the tumor and adjacent normal brain in glioblastoma patients undergoing simultaneous do...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-017-2445-5
更新日期:2017-06-01 00:00:00
abstract::Calcification is a rare phenomenon in high grade glioma (HGG). CT scans are sensitive to mineralization but used infrequently for tumor assessment in the MRI era. The presence of calcification can be overlooked on routine MRI. Calcification may reflect chronicity and natural changes in the tumor or its milieu over tim...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-015-1796-z
更新日期:2015-06-01 00:00:00
abstract::The insular cortex is located deep within the Sylvian fissure between multi-functional and structurally-compressed cerebral structures, and has been suggested to play an important role in both basic sensorimotor and complex social-emotional functions. Such structural and functional complexity presents a challenge for ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-014-1380-y
更新日期:2014-04-01 00:00:00
abstract::The optimal treatment of recurrent glioblastoma (GBM) in elderly patients is unclear. Fotemustine (FTM) is a third-generation nitrosourea showing efficacy in gliomas and it has been used with different schedules in adult patients. We performed, for the first time anywhere, a mono-institutional retrospective study to a...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-016-2136-7
更新日期:2016-07-01 00:00:00
abstract::While surgery is proned in low-grade glioma (LGG), the invasion of functional areas frequently prevents a complete resection. We report the first case of a patient operated on for a left frontal LGG, diagnosed because of seizures, with partial resection due to an invasion of the controlateral hemisphere. Chemotherapy ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-006-9168-3
更新日期:2006-11-01 00:00:00
abstract::In this review on current concepts in radiation therapy in the treatment of incompletely resected supratentorial low-grade glioma, a number of important issues are discussed. They include indication for radiation therapy, timing (early vs delayed), dose response issue, impact of modern neuroimaging, 'optimal' treatmen...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1023/a:1013333905202
更新日期:2001-11-01 00:00:00
abstract::Combination of procarbazine, lomustine and vincristine (PCV) with radiation therapy (RT) has been associated with longer survival in patients with anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), especially in those with chromosome 1p/19q codeletion. We report a multicenter retrospective study ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,多中心研究
doi:10.1007/s11060-013-1288-y
更新日期:2014-01-01 00:00:00
abstract::Meningiomas may display benign (Grade I), atypical (Grade II) and anaplastic (Grade III) histopathological findings. The cytogenetic studies strongly suggest that secondary changes (moreover loss of chromosome 22) appear to be associated with more atypical features and with greater clinical aggressivity. We studied 60...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/a:1006454107467
更新日期:2000-04-01 00:00:00
abstract::The use of radiotherapy alone to treat primary central nervous system lymphoma (PCNSL) does not produce the high local control and survival rates that it does in limited extranodal non-Hodgkin's lymphoma outside the central nervous system (CNS). Even with doses of whole brain radiation therapy (WBRT) to 40+20 Gy boost...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1023/a:1006206602918
更新日期:1999-07-01 00:00:00
abstract::Primary brain tumors cumulatively represent the most common solid tumors of childhood and are the leading cause of cancer related death in this age group. Traditionally, molecular findings and histological analyses from biopsies of resected tumor tissue have been used for diagnosis and classification of these diseases...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/s11060-014-1432-3
更新日期:2014-06-01 00:00:00
abstract::Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in the biology of malignant gliomas. To investigate mechanisms modulating PDGFR signaling in gliomagenesis, we employed a Drosophila glioma model and genetic screen to identify genes interacting with Pvr, the fly homolog of PDGFRs. Glial...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-015-1864-4
更新日期:2015-09-01 00:00:00
abstract::Cancer metastasis can affect any part of the nervous system. When the peripheral nervous system is involved, the usual targets are cranial nerves, nerve roots and plexi. However, peripheral nerves and muscles can also be affected by compression or infiltration of neoplastic cells. This review focuses in the diagnosis ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/s11060-004-8102-9
更新日期:2005-10-01 00:00:00
abstract:PURPOSE:Post-operative radiation therapy for brain metastases (BM) has become standard treatment. Concerns regarding the deleterious cognitive effects of Whole Brain Radiation Therapy spurred a trend to use focal therapies such as stereotactic radiosurgery (SRS). The purpose of this study was to prospectively evaluate ...
journal_title:Journal of neuro-oncology
pub_type: 临床试验,杂志文章
doi:10.1007/s11060-018-2954-x
更新日期:2018-11-01 00:00:00
abstract:INTRODUCTION:Informal family caregivers (FCG) are an integral and crucial human component in the cancer care continuum. However, research and interventions to help alleviate documented anxiety and burden on this group is lacking. To address the absence of effective interventions, we developed the electronic Support Net...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s11060-018-2909-2
更新日期:2018-09-01 00:00:00
abstract::Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treat...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s11060-014-1669-x
更新日期:2015-02-01 00:00:00
abstract::The completion of the Human Genome Project resulted in discovery of many unknown novel genes. This feat paved the way for the future development of novel therapeutics for the treatment of human disease based on novel biological functions and pathways. Towards this aim, we undertook a bioinformatics analysis of in-hous...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-010-0314-6
更新日期:2011-04-01 00:00:00
abstract:INTRODUCTION:To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains un...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-020-03461-4
更新日期:2020-05-01 00:00:00
abstract::Latino Americans are a rapidly growing ethnic group in the United States but studies of glioblastoma in this population are limited. We have evaluated characteristics of 21,184 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data fro...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,多中心研究
doi:10.1007/s11060-017-2377-0
更新日期:2017-04-01 00:00:00
abstract:OBJECTIVES:To study the inhibitory effects of plasmid-based siRNA targeting human epidermal growth factor receptor (EGFR) on tumor proliferation and invasion of TJ905 glioblastoma cells. METHODS:Two siRNA expression constructs targeting human EGFR extracellular domain (516-536) and catalytic domain (2400-2420) were tr...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-004-8322-z
更新日期:2005-09-01 00:00:00
abstract::This review identifies the current literature on the use of bevacizumab for cerebral radiation necrosis in patients with high-grade gliomas, summarizes the clinical course and complications following bevacizumab, and discusses the relative costs and benefits of this therapeutic option. A Medline search was conducted o...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/s11060-013-1233-0
更新日期:2013-12-01 00:00:00
abstract::The basement membrane collagen IV-degrading matrix metalloproteinases -2 and -9 (MMPs) are most often linked to the malignant phenotype of tumor cells by playing a critical role in invasion, metastasis, angiogenesis, and vasculogenesis. We verified the activity of these two MMPs in the sera of patients affected by bra...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-016-2297-4
更新日期:2017-01-01 00:00:00
abstract::The type III mutant epidermal growth factor receptor (EGFR) is expressed on the cell surface of a subset of glioma, but not of normal tissues. In this study, we investigated the in vivo kinetics of 3C10 mouse monoclonal antibody (mAb), specifically recognizing the type III mutant EGFR (EGFRvIII), using athymic nude mi...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/a:1024320516341
更新日期:2003-07-01 00:00:00
abstract:INTRODUCTION:There is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which is a harbor for adult neural stem cells, may be influenced by chemoradiation. The current diffusion-weighted imaging (DWI) study explored ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-020-03460-5
更新日期:2020-05-01 00:00:00
abstract::Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (≥10 years) from brain metastasis (BM). In this study, the records of 1953 patients who underwent treatment for BM with a potential for ≥10 years of follow-up were...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-016-2208-8
更新日期:2016-09-01 00:00:00
abstract::After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel-Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) contro...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/b:neon.0000014493.88402.dc
更新日期:2004-02-01 00:00:00
abstract::The authors report their personal experience with a surgical series of 16 cases of cerebral radiation-induced gliomas, defining diagnostic criteria and surgical and clinical characteristics. There were ten males and six females, with a median age of 45.9 years. Irradiation had initially been given for acute lymphoblas...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-008-9565-x
更新日期:2008-09-01 00:00:00