Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We ...now demonstrate that hypoxia-inducible factor HIF2α and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2α colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that
HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2α might represent a promising target for antiglioblastoma therapies.
Malignant gliomas are highly lethal cancers dependent on angiogenesis. Critical tumor subpopulations within gliomas share characteristics with neural stem cells. We examined the potential of stem ...cell-like glioma cells (SCLGC) to support tumor angiogenesis. SCLGC isolated from human glioblastoma biopsy specimens and xenografts potently generated tumors when implanted into the brains of immunocompromised mice, whereas non-SCLGC tumor cells isolated from only a few tumors formed secondary tumors when xenotransplanted. Tumors derived from SCLGC were morphologically distinguishable from non-SCLGC tumor populations by widespread tumor angiogenesis, necrosis, and hemorrhage. To determine a potential molecular mechanism for SCLGC in angiogenesis, we measured the expression of a panel of angiogenic factors secreted by SCLGC. In comparison with matched non-SCLGC populations, SCLGC consistently secreted markedly elevated levels of vascular endothelial growth factor (VEGF), which were further induced by hypoxia. In an in vitro model of angiogenesis, SCLGC-conditioned medium significantly increased endothelial cell migration and tube formation compared with non-SCLGC tumor cell-conditioned medium. The proangiogenic effects of glioma SCLGC on endothelial cells were specifically abolished by the anti-VEGF neutralizing antibody bevacizumab, which is in clinical use for cancer therapy. Furthermore, bevacizumab displayed potent antiangiogenic efficacy in vivo and suppressed growth of xenografts derived from SCLGC but limited efficacy against xenografts derived from a matched non-SCLGC population. Together these data indicate that stem cell-like tumor cells can be a crucial source of key angiogenic factors in cancers and that targeting proangiogenic factors from stem cell-like tumor populations may be critical for patient therapy.
Glioblastoma (GBM), the most common primary brain tumor in adults, is one of the most aggressive human cancers associated with high mortality. Standard treatments following diagnosis include surgical ...resection, radiotherapy and adjunctive chemotherapy. However, almost all patients develop disease progression following this multimodal therapy. Recent understanding in genomic and molecular abnormalities in GBM has shifted the treatment paradigm towards using molecularly targeted agents. One of the most prominent targets in cancer treatment is kinases, which can be commonly targeted by small molecule inhibitors or monoclonal antibodies. Despite the initial enthusiasm in exploring kinase inhibitors for GBM, first-generation kinase inhibitors that selectively disrupt single kinases have failed to demonstrate clinical benefit in most patients with GBM. Mechanisms of resistance may include genetic heterogeneity with cross-talk and coactivation of multiple signaling pathways, upregulation of alternative signaling cascades, limited drug delivery and existence of highly-resistant cellular subpopulations such as cancer stem cells. One strategy to circumvent this challenge is to target multiple kinases by multitargeted kinase inhibitors or combinations of single targeted kinase inhibitors, both of which have been evaluated in clinical trials for GBM.
The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular ...endothelial growth factor, in combination with irinotecan.
This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging.
The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli).
Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.
Malignant gliomas are lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes ...therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, L1CAM, in glioma stem cells as L1CAM regulates brain development and is expressed in gliomas. L1CAM(+) and CD133(+) cells cosegregated in gliomas, and levels of L1CAM were higher in CD133(+) glioma cells than normal neural progenitors. Targeting L1CAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133(+) glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for L1CAM regulation of cell survival as L1CAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and up-regulated the p21(WAF1/CIP1) tumor suppressor in CD133(+) glioma cells. To determine if targeting L1CAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted L1CAM in glioma cells before injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of L1CAM expression in vivo suppressed tumor growth and increased the survival of tumor-bearing animals. Together, these data show that L1CAM is required for maintaining the growth and survival of CD133(+) glioma cells both in vitro and in vivo, and L1CAM may represent a cancer stem cell-specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.
Primary central nervous system lymphoma (PCNSL) is a form of extranodal non-Hodgkin’s B-cell lymphoma limited to the CNS. The treatment of PCNSL is ineffective partly due to the blood-brain barrier ...(BBB) restriction of delivery of many drugs including anti-CD20 (Rituximab; RTX) which is a standard treatment for systemic B-cell lymphomas. In this study, liposome with tween-80 surface modification was fabricated and conjugated with RTX for enhancing BBB penetration to target lymphoma cells in the CNS. Physicochemical characterizations of Lip/RTX were performed and spherical shape liposomes with narrow size distribution were demonstrated by TEM. An average diameter of Lip/RTX was 168.57 ± 1.57 nm with the percentage of RTX conjugation at 90.94. Cell internalization monitored by flow cytometry confirmed that conjugation of RTX promoted liposome entry into Raji cells expressing CD20. Antitumor activity of Lip/RTX was comparable to free RTX indicating that RTX moieties on liposome remained their therapeutic function. In addition, Lip/RTX inhibited tumor aggressiveness by limiting cell migration and invasion. Systemic administration of Lip/RTX significantly prolonged survival of mice harboring intracranial lymphoma xenografts. Taken together, Lip/RTX presents a new potential treatment for patients with PCNSL.
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•Liposomal rituximab (Lip/RTX) was fabricated for precision treatment of primary CNS lymphoma.•Conjugation of RTX promoted liposome cell entry in Raji cells expressing CD20.•Lip/RTX retained therapeutic activity when compared with free RTX.•Lip/RTX inhibited tumor cell invasion via suppressing MMP-9 activity.•Lip/RTX significantly prolonged survival of mice bearing human PCNSL xenografts
Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available
salvage therapy. This study was conducted to determine if the ...combination of a novel antiangiogenic therapy, bevacizumab,
and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma.
Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence
of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab
and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was
determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m 2 , whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m 2 . Toxicity and response were assessed.
Results: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted
in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival
was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade
III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was
72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli,
and one patient had an arterial ischemic stroke.
Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.
Idiopathic Normal Pressure Hydrocephalus (iNPH) is a neurological condition that often presents gait disturbance in the early stages of the disease and affects other motor activities. This study ...investigated changes in temporospatial gait variables after cerebrospinal fluid (CSF) removal using a spinal tap test in individuals with idiopathic normal pressure hydrocephalus (iNPH), and explored if the tap test responders and non-responders could be clinically identified from temporospatial gait variables. Sixty-two individuals with iNPH were recruited from an outpatient clinic, eleven were excluded, leaving a total of 51 who were included in the analysis. Temporospatial gait variables at self-selected speed were recorded at pre- and 24-h post-tap tests which were compared using Paired t-tests, Cohen's d effect size, and percentage change. A previously defined minimal clinical important change (MCIC) for gait speed was used to determine the changes and to classify tap test responders and non-responders. A mixed model ANOVA was used to determine the within-group, between-group, and interaction effects. Comparisons of the data between pre- and post-tap tests showed significant improvements with small to medium effect sizes for left step length, right step time, stride length and time, cadence, and gait speed. Gait speed showed the largest percentage change among temporospatial gait variables. Within-group and interaction effects were found in some variables but no between-group effect was found. Tap test responders showed significant improvements in right step length and time, stride length and time, cadence, and gait speed while non-responders did not. Some individuals with iNPH showed clinically important improvements in temporospatial gait variables after the tap test, particularly in step/stride length and time, cadence, who could be classified by gait speed. However, gait-related balance variables did not change. Therefore, additional treatments should focus on improving such variables.
Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas ...with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent
CDKN2A/B
deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in
NF1
and
TP53
along with
IDH1/2
and
TERT
promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c)
TERT
promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
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