Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for ...single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
High-grade gliomas are deadly cancers, and current standard-of-care has demonstrated limited success. The ability to specifically target glioma cells allows for the development of safer and ...more efficacious brain cancer therapy strategies. Brevican, a CNS-specific extracellular matrix protein is upregulated in glioma cells and its expression correlates with tumor progression. Particularly, a brevican isoform lacking glycosylation, B/bΔg is a unique glioma marker and not expressed in non-cancerous tissues. Therefore, B/bΔg represents a valuable target for anti-cancer strategies. Here, we describe the utilization of state-of-the-art platforms to screen a one-bead-one-compound combinatorial peptide library to discover a novel “B/bΔg-Targeting Peptides”, called BTP-7 that can bind B/bΔg with high affinity and specificity. BTP-7 displayed 260 nanomolar affinity for recombinant B/bΔg protein. Binding to a specific site on B/bΔg was confirmed in a competitive binding assay using BTP-7 functionalized with a UV-crosslinker and BTP-7 had little association with the fully glycosylated isoform of brevican (control). Scrambling of the BTP-7 sequence led to complete abrogation of B/bΔg binding. Furthermore, BTP-7 is preferentially taken up by B/bΔg-expressing glioma cells compared with non-expressing cells. We also discovered that BTP-7 can cross the blood-brain barrier in both the in vitro BBB organoid model and in mice. BTP-7 displayed 10x greater binding to intracranial GBM-6 tumors than control peptides, and 4x higher tumor uptake than in normal brain tissues. Conjugation of BTP-7 to camptothecin (an anti-tumor drug) via a cleavable linker led to increased DNA damage in intracranial GBM-6 tumors and prolonged survival in tumor-bearing mice. Our results show the potential of BTP-7 for the development of next-generation targeted therapeutics that could greatly benefit the outcome of patients with advanced brain cancer.
Abstract
Recently, several Non-NF2 driver mutations (KLF4, TRAF7, SMO, AKT1E17K) in meningioma have been identified. While they have been shown to correlate with certain pathological subtypes and ...locations, the clinical impact and repercussions on cellular pathways have largely remained elusive. Through analysis of clinical, pathological and preoperative imaging data of 96 patients and sequencing of the corresponding 96 tumor samples for the Krueppel like factor 4-K409Q mutation (KLF4K409Q) we present evidence that the KLF4K409Q tumors harbour an increased risk for peritumoral brain edema (PTBE) and can be predicted with the edema-index, a simple tool based on preoperative imaging. Further analysis involving RNA-sequencing of a matched subset of 7 KLF4K409Q and 10 KLF4-wildtype (wt) tumors revealed a significant shift of gene expression and the upregulation of hypoxia driven pathways, including VEGF levels, in KLF4K409Q tumors. On the cellular level, we go on to show that the KLF4K409Q mutation results in an increased KLF-4 stability as well as the inhibition of hydroxylation dependent degradation of HIF1-α and a significant increase of VEGF expression under hypoxic conditions. Finally, we demonstrate that this upregulation of VEGF in KLF4K409Q cells can be inhibited by targeting the mammalian target of rapamycin (mTor) with Temsirolimus. In summary we show that the KLF4K409Q mutation in meningioma has highly relevant repercussions in both, the biological and clinical context and can be harnessed for targeted therapy.
Abstract
Several clinical trials are currently underway for patients with newly diagnosed and recurrent glioblastoma to reinvigorate tumor immunity using immune-checkpoint blockade. However, the CNS ...is immunologically unique in its maintenance of an immunosuppressive environment, to protect brain cells from autoimmunity and inflammation. Thus, immunotherapy of brain tumors requires novel regimens to overcome tumor immuno-suppression. Suitable preclinical animal models with exhausted tumor-specific immunity are currently not available. We thus hypothesized that a chronic LCMV (cLCMV) strain that induces T cell exhaustion in mice may be co-opted to model the impaired immunity that characterizes brain tumors. In this model, naïve and cLCMV-infected mice failed to reject a challenge with glioma in brain when murine glioma cells express one of LCMV antigens (VA-glioma) that are presented via MHC-I. In contrast, mice preimmunized with the acutely-controlled LCMV (aLCMV) strain did reject VA-glioma. In fact, in vitro co-culture of lymphocytes and glioma cells, and in vivo TIL analyses suggested that VA-glioma failed to induce CD8+ T cell responses in cLCMV-mice, in contrast to the robust CD8+ T cell response in aLCMV-mice. Furthermore, cLCMV-specific CD8 T cells lacked a central memory T cell phenotype (CD44+, CD62L-, CD127-) and expressed significantly high levels of PD-1. Thus, treatment with anti-PD1, but not isotype control antibody, successfully reinvigorated and restored antitumor immunity in cLCMV-mice that received VA-glioma cells. PD-1 blockade led to significantly improved survival. However, this treatment did not show a therapeutic effect in cLCMV-mice that received parental glioma cells that don't express the viral antigen. These data strongly suggest that PD-1 blockade is effective in brain tumors that induce impaired tumor-specific T cell immunity. In conclusion, this novel mouse model may be useful to screen for novel immune checkpoint inhibitors and combination regimes in the setting of a single dysfunctional CD8 T cell response.
Citation Format: Hiroshi Nakashima, Quazim Alayo, Pablo Penaloza, Dan Barouch, Ennio Antonio Chiocca. Establishment of a brain tumor model with dysfunctional tumor immunity in mice as a platform for immunotherapeutic evaluation and PD-1 immunotherapy. abstract. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A53.
The current state of glioma data registries Yearley, Alexander G; Iorgulescu, Julian Bryan; Chiocca, Ennio Antonio ...
Neuro-oncology advances,
01/2022, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
Background
The landscape of glioma research has evolved in the past 20 years to include numerous large, multi-institutional, database efforts compiling either clinical data on glioma ...patients, molecular data on glioma specimens, or a combination of both. While these strategies can provide a wealth of information for glioma research, obtaining information regarding data availability and access specifications can be challenging.
Methods
We reviewed the literature for ongoing clinical, molecular, and combined database efforts related to glioma research to provide researchers with a curated overview of the current state of glioma database resources.
Results
We identified and reviewed a total of 20 databases with data collection spanning from 1975 to 2022. Surveyed databases included both low- and high-grade gliomas, and data elements included over 100 clinical variables and 12 molecular data types. Select database strengths included large sample sizes and a wide variety of variables available, while limitations of some databases included complex data access requirements and a lack of glioma-specific variables.
Conclusions
This review highlights current databases and registries and their potential utility in clinical and genomic glioma research. While many high-quality resources exist, the fluid nature of glioma taxonomy makes it difficult to isolate a large cohort of patients with a pathologically confirmed diagnosis. Large, well-defined, and publicly available glioma datasets have the potential to expand the reach of glioma research and drive the field forward.
Abstract
BACKGROUND
Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess ...the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB).
METHODS
We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments.
RESULTS
Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference.
CONCLUSIONS
Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas
Abstract The Polestar N-20 Scanner (Medtronic Navigation, Louisville, CO) is an intraoperative magnetic resonance image (iMRI) guidance system designed for neurosurgery. Sixty-five patients underwent ...craniotomy for tumor resection using the iMRI during the period from April 2005 to December 2006. Anesthesiologists used an iMRI-compatible patient monitoring system (Veris MR, MEDRAD, Indianola, PA), anesthesia machine (Aestiva/5 MRI, Datex-Ohmeda, Madison, WI), and infusion pumps (Continuum; MEDRAD). Average setup time for each case (from intubation to incision) was one hour, 33 minutes and showed learning improvement over the 21-month period. The challenges facing the anesthesiologists in these cases included the need to use longer intravenous (IV) catheters and gas delivery and sampling lines, which increased dead space. Electrocardiographic signals became contaminated with electrical noise during iMRI scan procedures, which made it difficult to distinguish rhythm changes. None of our iMRI patients underwent a repeat resection, whereas the repeat resection rate for conventional tumor resection is reported to be as high as 30%. The use of a small, low-field iMRI system provided adequate imaging for resection of lesions without the need of repeat resections in the weeks following the initial procedure, and did not significantly alter the anesthetic procedure. A team effort between the anesthesiologists, surgeons, nurses, and MRI technicians is paramount for the practical and efficient use of these iMRI systems.
Background: EVs are commonly characterized by nanoparticle analysis (NTA), electron microscopy and immunoblot detection of vesicle markers (i.e. CD9, CD81, CD63, Annexin V). It is unclear, however, ...to what extent marker profiles overlap and how useful they are for distinguishing different cell types of origin. With the goal of defining markers that allow enrichment of cancer EVs from patient blood, we utilized imaging flow cytometry (IFC) to discriminate single EVs via multiple surface markers. Methods: EVs were isolated from blood of cancer patients (n = 25), healthy controls (n = 20), PALM-GFP-GL261 and PALM-GFP-CT2A brain tumour-bearing mice (n = 5), cancer cell cultures (n = 12), neural stem cells (NSC), cerebral endothelial cells (cEC) and T-cells (n = 4). EVs were analysed by IFC, immunoblotting, electron microscopy and NTA. Results: IFC allows the detection of up to four different markers on single EVs sized <200 nm, including CD9, CD81, CD63 and Annexin V, and allows the discrimination of different EV subpopulations present in human and murine plasma and in cell culture supernatants. Circulating plasma EVs in patients and controls as well as in mice are primarily CD9 positive, whereas CD81 and CD63 distinguish different subpopulations. Interestingly, cancer patients exhibit increased levels of circulating EV compared to aged-matched healthy controls (p < 0.001), as measured by NTA and IFC. In particular, double-positive EVs (i.e. CD9+/CD81+) are elevated in cancer patients (p = 0.018) vs healthy controls, whereas single-positive EVs are not. In accordance with these findings, cancer cell lines excrete increased levels of double positive EVs in vitro, whereas NSCs and cECs primarily produce CD9+ EVs, and T-cells predominantly release CD81+ EVs. Summary/Conclusion: EVs can be characterized by IFC, a unique technique that facilitates the discrimination of different EV subpopulations. The identification and classification of different circulating EV populations is an essential step towards capitalizing the potential of tumour-derived EVs as biomarkers which are easily accessible by liquid biopsy.
A hallmark of malignant gliomas is their ability to disperse through neural tissue, leading to long-term failure of all known therapies. Identifying new antimigratory targets could reduce glioma ...recurrence and improve therapeutic efficacy, but screens based on conventional migration assays are hampered by the limited ability of these assays to reproduce native cell motility. Here, we have analyzed the motility, gene expression, and sensitivity to migration inhibitors of glioma cells cultured on scaffolds formed by submicron-sized fibers (nanofibers) mimicking the neural topography. Glioma cells cultured on aligned nanofiber scaffolds reproduced the elongated morphology of cells migrating in white matter tissue and were highly sensitive to myosin II inhibition but only moderately affected by stress fiber disruption. In contrast, the same cells displayed a flat morphology and opposite sensitivity to myosin II and actin inhibition when cultured on conventional tissue culture polystyrene. Gene expression analysis indicated a correlation between migration on aligned nanofibers and increased STAT3 signaling, a known driver of glioma progression. Accordingly, cell migration out of glioblastoma-derived neurospheres and tumor explants was reduced by STAT3 inhibitors at subtoxic concentrations. Remarkably, these inhibitors were ineffective when tested at the same concentrations in a conventional two-dimensional migration assay. We conclude that migration of glioma cells is regulated by topographical cues that affect cell adhesion and gene expression. Cell migration analysis using nanofiber scaffolds could be used to reproduce native mechanisms of migration and to identify antimigratory strategies not disclosed by other
in vitro
models.
PDF
