Glioblastoma Multiforme Therapy Research Articles

Identification of Systems Level Molecular Signatures from Glioblastoma Multiforme Derived Extracellular Vesicles.

Glioblastoma multiforme (GBM) is one of the most lethal malignancies of the central nervous system characterized by high mortality rate. The complexity of GBM pathogenesis, progression, and prognosis is not fully understood yet. GBM-derived extracellular vesicles (EVs) carry several oncogenic elements that facilitate GBM progression. The purpose of this study was to identify systems level molecular signatures from GBM-derived EVs using integrative analysis of publicly available transcriptomic data generated from plasma and serum samples. The dataset contained 19 samples in total, of which 15 samples were from plasma (11 GBM patients and 4 healthy samples) and 4 samples were from serum (2 GBM and 2 healthy samples). We carried out statisticalanalysis to identify differentially expressed genes (DEGs),functional enrichment analysis of the DEGs, protein-protein interaction networks, module analysis, transcription factors and target gene regulatory networks analysis, and identification of hub genes. The differential expression of the identified hub genes were validated with the independent TCGA-GBM dataset. We have identified afew crucial genes and pathways associated with GBM prognosis and therapy resistance. The DEGs identified from plasma were associated with inflammatory processes and viral infection. On the other hand, the hub genes identified from the serum samples were significantly associated with protein ubiquitinylation processes and cytokine signaling regulation. The findings indicate that GBM-derived plasma and serum DEGs may be associated with distinct cellular processes and pathways which facilitate GBM progression. The findings will provide better understanding of the molecular mechanisms of GBM pathogenesis and progression. These results can further be utilized for developing and validating minimally invasive diagnostic and therapeutic molecular biomarkers for GBM.

Molecular Targets and Nanoparticulate Systems Designed for the Improved Therapeutic Intervention in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most aggressive and fatal CNS related tumors, which is responsible for about 4% of cancer-related deaths. Current GBM therapy includes surgery, radiation, and chemotherapy. The effective chemotherapy of GBM is compromised by two barriers, i. e., the blood-brain barrier (BBB) and the blood tumor barrier (BTB). Therefore, novel therapeutic approaches are needed. Nanoparticles are one of the highly efficient drug delivery systems for a variety of chemotherapeutics that have gained massive attention from the last three decades. Perfectly designed nanoparticles have the ability to cross BBB and BTB and precisely deliver the chemotherapeutics to GBM tissue/cells. Nanoparticles can encapsulate both hydrophilic and lipophilic drugs, genes, proteins, and peptides, increase the stability of drugs by protecting them from degradation, improve plasma half-life, reduce adverse effects and control the release of drugs/genes at the desired site. This review focussed on the different signaling pathways altered in GBM cells to understand the rationale behind selecting new therapeutic targets, challenges in the drug delivery to the GBM, various transport routes in brain delivery, and recent advances in targeted delivery of different drug and gene loaded various lipidic, polymeric and inorganic nanoparticles in the effective management of GBM.

Hsa_circ_0043278 functions as competitive endogenous RNA to enhance glioblastoma multiforme progression by sponging miR-638.

Circular RNAs have a critical function in the pathogenesis of many diseases and can function as competing endogenous RNA or miRNA sponges to inhibit miRNA and therefore upregulate the expression of target genes. However, little is known about the role of has_circRNA_0043278 (circ_0043278) in glioblastoma multiforme (GBM) and its potential downstream miRNA targets. This work validated that circ_0043278 is highly expressed in GMB cell lines and tissues, while knockdown circ_0043278 inhibited GBM cell migration, proliferation, and invasion in vitro and tumorigenesis in vivo. Dual-luciferase reporter assay determined that circ_0043278 directly sponged miR-638 to upregulate the expression of HOXA9, which can activate downstream Wnt/β-catenin signaling in GBM. Moreover, miR-638 inhibition reversed circ_0043278 silencing-induced impairment of malignant tumor behavior. These results showed that circ-0043278/miRNA-638/ Homeobox A9 (HOXA9) axis had a vital function in promoting GBM progression. Our findings may provide potential new targets for the diagnosis and therapy of GBM.

Preoperative Prognostic Stratification In GBM Patients Using Inverse Distance-Based Proximity To Stem Cell Niches

Glioblastoma multiforme (GBM) is the most lethal brain cancer in adults, with a high local recurrence rate despite surgery and chemoradiotherapy. Emerging evidence has linked tumor aggressiveness with the involvement of stem cell niches (SCN) that vary by patient. However, existing SCN research insufficiently quantifies the geometrical relationship between all SCN zones and the tumor for personalized risk assessment and potentially more effective therapy. This study aims to establish such relationship in brain GBM patients using MRI inverse distance map. Preoperative T1 MRI scans and pre-labeled tumor regions of 102 patients from the publicly available BRATS2017 dataset were used in this study. SCN segmentation, including bilateral subventricular zones and subgranular zones, were manually defined in the Montreal Neurological Institute (MNI) brain template. Based on the binary SCN segmentations, a proximity map was generated using the sum of the power 1 inverse distance weightings to all observations in SCNs, normalized between 0 and 1. All MR scans were transformed into the MNI space in Advanced Normalization Tools (ANTs) using affine alignment followed by symmetric normalization based lesion excluded deformable registration. The resulted transformations were propagated to each tumor segmentation to calculate the mean proximity score (PS), whose prognostic capacity was then evaluated using Cox proportional hazards regression with overall survival (OS) and Log-rank tests between sorted and evenly divided high-risk and low-risk groups. As a comparison, the same analyses were conducted on traditional stem cell niches related features, including tumor edge to the ventricle (EV) and center to the ventricle (CV). PS is correlated with OS with a hazardous ratio (HR) of 4.45 and a p-value of 0.0297, indicating a significant inverse relationship between SCN proximity and survival. In contrast, neither EV nor CV is significantly correlated with OS, with HR = 0.9676, p = 0.7483 and HR = 0.9884, p = 0.5660, respectively. Furthermore, the log-rank test for patients stratified by PS reveals a significant difference in survival risk (log-rank p = 0.0474), while stratification using either EV (log-rank p = 0.1486) or CV ((log-rank p = 0.5829) fails to result in significant differences. We introduced a novel inverse distance-based metric, proximity score, to more effectively characterize GBM tumor to SCN zones geometrical relationships. Proximity score outperformed traditional edge or center distance-based measurements in OS prediction and risk stratification. With the improved quantification, PS may be used for better personalized GBM risk assessment and therapy.

156 Poster - The role of enhancer RNAs in glioblastoma multiforme

Background: Glioblastoma Multiforme (GBM) represents the most aggressive type of human brain cancer with dismal prognosis. Studies have revealed the presence of self-propagating cancer stem cells which exhibit increased phenotypic plasticity under the influence of the tumor microenvironment. Common therapies for GBM include surgical resection, radiation and adjuvant chemotherapy. Despite these therapeutic efforts, GBM has a 5-year survival of about 5%. Although DNA (genetic) variations account for 30– 50% of the abnormalities identified in GBM and other cancers, epigenetic abnormalities such as histone modifications and non-coding RNA species account for the remaining drivers of cancer. A decade ago, a new class of non-coding RNA termed enhancer RNA (eRNA) was discovered. It is accepted that the combinatorial binding of RNA Pol II and the histone mark H3K27Ac at specific enhancer regions mark active enhancers that can produce eRNAs. Multiple articles have demonstrated the presence and role of eRNAs in breast cancer, prostate cancer and macrophages; the main role being the regulation of gene transcription through stabilization of enhancer-promoter looping. However, the functional role of eRNAs in the maintenance of the glioma stem cell fate and the contribution of eRNAs to the reversible phenotypic transition of glioma stem cells are not known. We hypothesize that eRNAs are expressed in glioma stem cells and may modulate the activity of neighboring and stemness essential genes as well as regulate genome organization.

Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells.

Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with doxorubicin showed promising results. Doxorubicin, however, is not used first-line in GBM therapy. Therefore, we analyzed the cytotoxic effect of methadone alone and in combination with temozolomide, a DNA-alkylating drug that is first-line used in GBM treatment, utilizing GBM-derived cell lines and a human fibroblast cell line. We show that methadone is cytotoxic on its own, inducing apoptosis and necrosis, which was observed at a concentration above 20 µg/mL. Methadone was similar toxic in isogenic MGMT expressing and non-expressing cells, and in LN229 glioblastoma and VH10T human fibroblasts. The apoptosis-inducing activity of methadone is not bound on the opioid receptor (OR), since naloxone, a competitive inhibitor of OR, did not attenuate methadone-induced apoptosis/necrosis. Administrating methadone and temozolomide together, temozolomide had no impact on methadone-induced apoptosis (which occurred 3 days after treatment), while temozolomide-induced apoptosis (which occurred 5 days after treatment) was unaffected at low (non-toxic) methadone concentration (5 µg/mL), and at high (toxic) methadone concentration (20 µg/mL) the cytotoxic effects of methadone and temozolomide were additive. Methadone is not genotoxic, as revealed by comet and γH2AX assay, and did not ameliorate the genotoxic effect of temozolomide. Further, methadone did not induce cellular senescence and had no effect on temozolomide-induced senescence. Although methadone was toxic on senescent cells, it cannot be considered a senolytic drug since cytotoxicity was not specific for senescent cells. Finally, we show that methadone had no impact on the MGMT promoter methylation. Overall, the data show that methadone on glioblastoma cells in vitro is cytotoxic and induces apoptosis/necrosis at doses that are above the level that can be achieved in vivo. It is not genotoxic, and does not ameliorate the cell killing or the senescence-inducing effect of temozolomide (no synergistic effect), indicating it has no impact on temozolomide-induced signaling pathways. The data do not support the notion that concomitant methadone treatment supports temozolomide-based chemotherapy.

Biological Characterization and Therapeutics for Subscalp Recurrent in Intracranial Glioblastoma.

PurposeGliomas are common intracranial tumors, of which 70% are malignant gliomas. Glioblastoma multiforme (GBM) is the most aggressive tumor, and patients with GBM have a median survival time of only 9–12 months; extracranial recurrence of GBM is very rare. A therapeutic strategy for this kind of recurrent tumor is lacking.Materials and MethodsWe present a case of a patient with extracranial recurrence of subscalp GBM. The subscalp tumor was resected and xenotransplanted into BALB/C nude mice. Then, glioma cells were isolated from the xenograft models and passaged in vitro. HE staining, immunohistochemistry, CCK-8 assays, karyotypic analysis, short tandem repeat STR analysis and flow cytometry were used to analyze the biological characteristics and malignant phenotype of these established cells. The cells and xenografts were then used as preclinical models to evaluate the antitumor efficacy of oncolytic herpes simplex virus 1 (oHSV-1).ResultsThe isolated cells, which were named BT-01, were positive for Nestin and GFAP. The main characteristics of BT-01 cells were that they harbored glioblastoma stem-like cells (GSCs) and that they possessed highly aggressive migration capacities compared with the existing cell lines U87-MG and U251-MG. Moreover, BT-01 cells tolerated the chemotherapeutic drug temozolomide. Our study showed that oHSV-1 could replicate in and repress the growth of BT-01 cells and significantly inhibit tumor growth in xenograft models.ConclusionTaken together, our results showed that a new recurrent glioblastoma cell line was established, which can be useful for research on recurrent glioblastoma. We provided a reliable preclinical model to evaluate the antitumor efficacy of oHSV-1 in vivo and a promising therapy for recurrent GBM.

Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster.

Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection. A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical-chemical properties of the ICS were systematically evaluated. Efficacy of photodynamic therapy (PDT) was evaluated in vitro with GL261 cells and in vivo in a subtotal resection trial using a syngeneic flank tumor model. NIR imaging properties of ICS were evaluated in both a flank and an intracranial GBM model. ICS demonstrated high ICG and Ce6 encapsulation efficiency, high payload capacity, and chemical stability in physiologic conditions. In vitro cell studies demonstrated significant PDT-induced cytotoxicity using ICS. Preclinical animal studies demonstrated that the nanoclusters can be detected through NIR imaging in both flank and intracranial GBM tumors (ex: 745nm, em: 800nm; mean signal-to-background 8.5 ± 0.6). In the flank residual tumor PDT trial, subjects treated with PDT demonstrated significantly enhanced local control of recurrent neoplasm starting on postoperative day 8 (23.1 mm3 vs 150.5 mm3, p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 mm3 vs 806.1 mm3 on day 23 (p = 0.0055). A multimodal theragnostic agent comprised solely of FDA-approved components was developed to couple optical imaging and PDT. The findings demonstrated evidence for the potential theragnostic benefit of ICS in surgical oncology that is conducive to clinical integration.

Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM.

Abstract 4769: Mapping cellular metabolic activity within U87MR glioblastoma cells in response to chemical and environmental insult using label-free quantitative phase imaging

Abstract Introduction: One of our drug development target diseases is Glioblastoma multiforme (GBM), a serious neurological disease with a very poor prognosis for the patients due, in part, to the large number of metabolic pathways it can follow. Materials and Methods: We are using U87-MR cells as a model. We employ time-lapse quantitative phase imaging technology that quantifies the refractive index (RI) of cells via light interference. There is no need for labeling of the cells. The RI is an intrinsic physical property of the cells which lends itself to highly precise and accurate quantitative analysis. Our basic protocol involves seeding cells, providing atmosphere and temperature control. Time-lapse images are automatically obtained at intervals ranging from 10 seconds up to 5 minutes and over time periods from minutes to days. Cells are unlabeled, and can be untreated, or treated with drugs or components of multi-drug formulations. We used drugs that have known effects on the cell cycle, mitochondria and induce apoptosis. We also tested drugs such as temozolomide (TMZ) the first line regimen in GBM therapy protocols. Results: Our first notable finding relates to U87-MR motility. The cells self-assemble into a pattern of well separated cell clusters with tubular connections. These connections are initiated by mitochondrial tunneling and are stable over time. The tunnels are reinforced with actin, and mitochondrial fusion occurs at substrate contact foci. These connections between cells also are conduits for intercellular communication and the transport of objects such as mitochondria (MT). Many drugs that have nuclear targets, including demecolcine, topoisomerase inhibitors, present effects in the cytoplasm of the cells, including vacuoles and possible the remnants of DNA repair. MT contain their DNA. The necessary genes are needed to control their own replication to replace damaged MT and to initiate alternative energy sources, such as mitophagy where cellular protein digestion is utilized as a source of energy. There are numerous factors that cause a wide range of textures within cells, including MT fission, lipid droplets, and autophagy. In many treatments, we see a definite region forming with very active textural changes. Due to its proximity to the nuclear membrane as well as the endoplasmic reticulum, we hypothesize that this may be where mTOR1 and mTOR2C activities originate. In the TMZ studies, we found a strong correlation between the dosage, and the morphology of the cells with a transformation to mesenchymal morphologies at the higher dosages. Discussion: GBM cells adapt to and control a number of different metabolic pathways which are primarily characterized by biochemical analysis. We have vastly improved-time lapse imaging capabilities. We produced first evidence of successful characterization of the metabolic changes based on RI quantifications and visual effects. Citation Format: Ed Luther, Livia P. Mendes, Vladimir P. Torchilin. Mapping cellular metabolic activity within U87MR glioblastoma cells in response to chemical and environmental insult using label-free quantitative phase imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4769.

Combination Therapy with Nanomicellar-Curcumin and Temozolomide for In Vitro Therapy of Glioblastoma Multiforme via Wnt Signaling Pathways.

Glioblastoma (GBM) is the most serious brain tumor and shows a high rate of drug resistance. Wnt signaling is a very important pathway in GBM that can activate/inhibit other pathways, such as apoptosis and autophagy. In this study, we evaluated the efficacy of a combination of temozolomide (TMZ) plus curcumin or nanomicellar-curcumin on the inhibition of GBM growth in vitro, via effects on autophagy, apoptosis, and the Wnt signaling pathway. Two concentrations of curcumin and nanomicellar-curcumin (i.e., 20μM and 50μM) alone, and in combination with TMZ (50μM) were used to induce cytotoxicity in the U87 GBM cell line. Wnt signaling-, autophagy-, and apoptosis-related genes were assessed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blots. All treatments (except 20μM curcumin alone) significantly decreased the viability of U87 cells compared to controls. Curcumin (50μM), nanomicellar-curcumin alone and in combination with TMZ significantly decreased the invasion and migration of U87 cells. Autophagy-related proteins (Beclin 1, LC3-I, LC3-II) were significantly increased. Apoptosis-related proteins (Bcl-2 and caspase 8) were also significantly increased, while Bax protein was significantly decreased. The expression levels of Wnt pathway-associated genes (β-catenin, cyclin D1, Twist, and ZEB1) were significantly reduced.

Advances in histone deacetylase inhibitors in targeting glioblastoma stem cells.

Glioblastoma multiforme (GBM) is a lethal grade IV glioma (WHO classification) and widely prevalent primary brain tumor in adults. GBM tumors harbor cellular heterogeneity with the presence of a small subpopulation of tumor cells, described as GBM cancer stem cells (CSCs) that pose resistance to standard anticancer regimens and eventually mediate aggressive relapse or intractable progressive GBM. Existing conventional anticancer therapies for GBM do not target GBM stem cells and are mostly palliative; therefore, exploration of new strategies to target stem cells of GBM has to be prioritized for the development of effective GBM therapy. Recent developments in the understanding of GBM pathophysiology demonstrated dysregulation of epigenetic mechanisms along with the genetic changes in GBM CSCs. Altered expression/activity of key epigenetic regulators, especially histone deacetylases (HDACs) in GBM stem cells has been associated with poor prognosis; inhibiting the activity of HDACs using histone deacetylase inhibitors (HDACi) has been promising as mono-therapeutic in targeting GBM and in sensitizing GBM stem cells to an existing anticancer regimen. Here, we review the development of pan/selective HDACi as potential anticancer agents in targeting the stem cells of glioblastoma as a mono or combination therapy.

Novel N-cadherin antagonist causes glioblastoma cell death in a 3D bioprinted co-culture model

Glioblastoma multiforme (GBM) is a deadly type of brain cancer. There is a need to identify novel therapies for GBM as current treatments only marginally increase survival. Modelling the complexity of cancerous tissues using 3D bioprinted constructs serves as a novel approach for preclinical testing of anticancer drugs. A novel small molecule antagonist of the cell adhesion molecule, N-cadherin (NCAD), (S)-1-(3,4-Dichlorophenoxy)-3-(4-((S)-2-hydroxy-3-(4-methoxyphenoxy)propylamino)piperidin-1-yl)propan-2-ol has shown promise as an anticancer agent. This study investigated the influence of this antagonist on GBM cells bioprinted with astrocytes into 3D constructs. The NCAD antagonist prevented spheroid formation and induced cell death in the 3D model. This is the first demonstration that an NCAD antagonist can cause GBM cell death.

Xanthohumol regulates miR-4749-5p-inhibited RFC2 signaling in enhancing temozolomide cytotoxicity to glioblastoma

AimsXanthohumol (XN), a natural prenylated flavonoid isolated from Humulus lupulus L. (hops), possess the therapeutic effects in glioblastoma multiforme (GBM), which is a grade IV aggressive glioma in adults. However, low bioavailability and extractive yield limit the clinical applications of XN. To comprehensively investigate XN-mediated gene networks in inducing cell death is helpful for drug development and cancer research. Therefore, we aim to identify the detailed molecular mechanisms of XN's effects on exhibiting cytotoxicity for GBM therapy. Methods and key findingsXN significantly induced GBM cell death and enhanced temozolomide (TMZ) cytotoxicity, a first-line therapeutic drug of GBM. XN-mediated transcriptome profiles and canonical pathways were identified. DNA repair signaling, a well-established mechanism against TMZ cytotoxicity, was significantly correlated with XN-downregulated genes. Replication factor C subunit 2 (RFC2), a DNA repair-related gene, was obviously downregulated in XN-treated cells. Higher RFC2 levels which occupied poor patient survival were also observed in high grade GBM patients and tumors. Inhibition of RFC2 reduced cell viability, induced cell apoptosis, and enhanced both XN and TMZ cytotoxicity. By intersecting array data, bioinformatic prediction, and in vitro experiments, microRNA (miR)-4749-5p, a XN-upregulated microRNA, was identified to target to RFC2 3′UTR and inhibited RFC2 expression. A negative correlation existed between miR-4749-5p and RFC2 in GBM patients. Overexpression of miR-4749-5p significantly promoted XN- and TMZ-mediated cytotoxicity, and reduced RFC2 levels. SignificanceConsequently, we suggest that miR-4749-5p targeting RFC2 signaling participates in XN-enhanced TMZ cytotoxicity of GBM. Our findings provide new potential therapeutic directions for future GBM therapy.

Lumefantrine, an antimalarial drug, reverses radiation and temozolomide resistance in glioblastoma

Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.

Designing Biodegradable Wafers Based on Poly(L-lactide-co-glycolide) and Poly(glycolide-co-\u03b5-caprolactone) for the Prolonged and Local Release of Idarubicin for the Therapy of Glioblastoma Multiforme

PurposeThe blood-brain barrier limits the application of idarubicin in the therapy of glioblastoma multiforme. Biodegradable, intracranial wafers with prolonged release may increase therapy efficiency.MethodsBlank wafers, wafers containing 5% w/w and 10% w/w of idarubicin were formulated by solution casting from poly(L-lactide-co-glycolide) and poly(glycolide-co-ε-caprolactone). The following methods were used: NMR, GPC, DSC, FTIR, AFM, UV-VIS, and a viability and proliferation assay for idarubicin action (U87MG cell line).ResultsWafers showed a surface with numerous immersions and hills. A lack of interactions between idarubicin and the copolymers was observed. The substance was entrapped in the matrix and released in two phases for all wafers with the appropriate bolus and maintenance dose. The burst effect was observed for all wafers, however, the biggest bolus for poly(L-lactide-co-glycolide) wafers containing 5% w/w of idarubicin was noted. The stable and steady degradation of poly(glycolide-co-ε-caprolactone) wafers containing 5% w/w of idarubicin ensures the most optimal release profile and high inhibition of proliferation.ConclusionsCopolymer wafers with idarubicin are an interesting proposition with great potential for the local treatment of glioblastoma multiforme. The release rate and dose may be regulated by the amount and kind of wafers for various effects.

CN4 INVESTIGATING PROGRESSION-FREE SURVIVAL AS A POTENTIAL SURROGATE ENDPOINT FOR OVERALL SURVIVAL IN FIRST-LINE TREATMENT FOR GLIOBLASTOMA MULTIFORME: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Due to unmet therapeutic needs in glioblastoma multiforme (GBM), identification of earlier endpoints for evaluating new therapies is desirable. Given that progression-free survival (PFS) is an earlier assessable endpoint than overall survival (OS), we evaluated whether PFS could act as a surrogate for OS among first-line therapies for GBM.

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism

Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G2/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.

The CXCL12/CXCR4 axis confers temozolomide resistance to human glioblastoma cells via up-regulation of FOXM1

Glioblastoma multiforme (GBM) is the most common primary malignancy in the adult central nervous, and is characterized by high aggressiveness and a high mortality rate. The high mortality rate is largely due to the development of drug resistance. Temozolomide (TMZ) resistance is considered to be one of the major reasons responsible for GBM therapy failure. CXCL12/CXCR4 has been demonstrated to be involved in cell proliferation, migration, invasion, angiogenesis, and radioresistance in GBM. However, its role in TMZ resistance in GBM is unknown. In this study, we aimed to evaluate the role of CXCL12/CXCR4 in mediating the TMZ resistance to GBM cells and explore the underlying mechanisms. We found that the CXCL12/CXCR4 axis enhanced TMZ resistance in GBM cells. Further study showed that CXCL12/CXCR4 conferred TMZ resistance and promoted the migration and invasion of GBM cells by up-regulating FOXM1. This resistance was partially reversed by suppressing CXCL12/CXCR4 and FOXM1 silencing. Our study revealed the vital role of CXCL12/CXCR4 in mediating the resistance of GBM cells to TMZ, and suggested that targeting CXCL12/CXCR4 axis may attenuate the resistance to TMZ in GBM.

H2S Photosystems in the Treatment of Glioblastoma

Glioblastoma multiforme (GBM) is the most frequent and deadly primary malignant central nervous system (CNS) tumour in adults. GBM is usually treated through the reduction of tumour mass and cerebral decompression, together with radiotherapy and chemotherapy, which improve the quality of life of the subject and prolong its survival. Treatment remains challenging, as GBM inevitably re‐emerges despite surgical debulking, radiotherapy and chemotherapy. Therefore, the discovery of effective therapy for GBM is an area of interest. Photothermal therapy (PTT) is a newly developed and encouraging therapeutic strategy, in treating cancer. Gold nanorods (AuNRs) are ideal nanomaterials for PTT applications both in vitro and in vivo. There is a reasonable body of evidence suggesting that endogenous H2S production is important for the growth and proliferation of colon and ovarian cancer. A limited number of studies are available in CNS cancer. Photoresponsive systems that delivers H2S on demand were used to treat glioblastoma to design and generate compounds based on photo‐thermal release of H2S that act as anti‐cancer therapy for glioblastoma. AuNRDs were prepared by a modified procedure based on the seed assisted method. These systems were tailored with a thiolate spacer appendages to permit the covalently link to the AuNRDs surface. The dual H2S photoactive‐systems were characterized by electronic microscopy methods, optical absorption, and emission techniques. Photocontrolled H2S‐based therapies were tested on GBM cell lines U87, A172, U138, LN‐18, T98G, U118‐MG. Measurement of H2S relase, Cell Cycle Analysis, Comet assay, determination of intracellular ROS, and apoptotic pathways were performed. Moreover, xenograft and orthotopic model were used to demonstrated the effect of dual H2S photoactive‐systems on tumour volume and weight, neoangiogenesis, tissue invasion. Animals were also subjected to magnetic resonance imaging. Photocontrolled H2S‐based therapies could emerge as new unconventional treatment modalities that complement better‐known photodynamic and photothermal therapies. Nanosystems carrying chemotherapeutic drugs or as mediators of alternative therapies offer several advantages over the standard dosing forms in the treatment of GBM.Support or Funding Informationno funding