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Doxorubicin is a prototypical inducer of immunogenic cell death (ICD) that sensitizes to subsequent immunotherapy by PD-1 blockade. However, this systemic drug combination fails against glioblastoma, hidden behind the blood-brain barrier (BBB). A recent work delineates a biophysical method for BBB permeabilization that yields effective preclinical effects of chemoimmunotherapy., Competing Interests: J.G.P. is the inventor of patents covering the diagnosis, prognosis, and treatment of cancers, including patents licensed to Turnstone Biologics and Therafast Bio. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds, and Rejuveron Life Sciences. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. GK’s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk, and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

GBM is one of the most malignant tumor in central nervous system. The resistance to temozolomide (TMZ) is inevitable in GBM and the characterization of TMZ resistance seriously hinders clinical treatment. It is worthwhile exploring the underlying mechanism of aggressive invasion and TMZ resistance in GBM treatment. Bioinformatic analysis was used to analyze the association between RND1 and a series of EMT-related genes. Colony formation assay and cell viability assay were used to assess the growth of U87 and U251 cells. The cell invasion status was evaluated based on transwell and wound-healing assays. Western blot was used to detect the protein expression in GBM cells. Treatment targeted RND1 combined with TMZ therapy was conducted in nude mice to evaluate the potential application of RND1 as a clinical target for GBM. The overexpression of RND1 suppressed the progression and migration of U87 and U251 cells. RND1 knockdown facilitated the growth and invasion of GBM cells. RND1 regulated the EMT of GBM cells via inhibiting the phosphorylation of AKT and GSK3-β. The promoted effects of RND1 on TMZ sensitivity was identified both in vitro and in vivo . This research demonstrated that the overexpression of RND1 suppressed the migration and EMT status by downregulating AKT/GSK3-β pathway in GBM. RND1 enhanced the TMZ sensitivity of GBM cells both in vitro and in vivo . Our findings may contribute to the targeted therapy for GBM and the understanding of mechanisms of TMZ resistance in GBM.

The spices and aromatic herbs were used not only in cooking to add flavour and smell to dishes but also for medicinal use. Nigella sativa, also called black cumin, is one of the species that contains an important bioactive component, thymoquinone (TQ), which has antioxidant, anti-inflammatory, antimicrobial, and antidiabetic effects. Curcuma longa, which also includes curcumin, has numerous anti-cancer properties. However, the bioavailability of curcumin is lower than that of its analogs. An analog of curcumin (EF-24), which has better bioavailability than curcumin, is capable of exerting a high anti-cancer effect. In our study, we determined the effects of PON1 enzyme activity on the proliferation and aggressiveness of glioblastoma cancer treated with TQ and EF-24 from lysates of the glioblastoma cell line U87MG. The results were determined as increased PON1 activity after treatment with TQ and EF-24 in the U87MG cell line ( p  < 0.0001).

Background: Temozolomide (TMZ) is an alkylating agent approved for the management of glioblastoma. The TMZ is not known for progressive multifocal leukoencephalopathy (PML). The main objective of the current study is to find out the association of TMZ with PML using disproportionality analysis of FDA Adverse Event Reporting System (FAERS) data integrated with network pharmacological approaches., Research Design and Methods: OpenVigil tool was used to query the FAERS database. The disproportionality measures were calculated. The network has been constructed using Cytoscape. Finally, the possible binding interactions were studied using Glide, Schrödinger Inc., Results: A total number of 3502 cases of PML were reported in the FAERS database. Out of these, 10 cases were found with TMZ. The subgroup analysis results have shown a greater number of cases in females. The network has indicated the involvement of human mitogen-activated protein kinase, 3-phosphoinositide-dependent protein kinase 1 protein, human mTOR complex protein, phosphatidylinositol 4,5-bisphosphate 3-kinase protein, and glycogen synthase kinase-3 beta protein. The docking results have indicated good interactions of TMZ with active site of glycogen synthase kinase-3 beta and mitogen-activated protein kinase 1 as compared to other identified targets., Conclusion: The PML is identified as novel signal with temozolomide.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients., Competing Interests: M.L. has received research support from Arbor, BMS, Accuray, Tocagen, Biohaven, Kyrin-Kyowa and Biohaven, has been a consultant to Tocagen, VBI, InCephalo Therapeutics, Pyramid Bio, Merck, BMS, Insightec, Biohaven, Sanianoia, Hemispherian, Black Diamond Therapeutics, Novocure, is a shareholder of Egret Therapeutics and has patents for Focused radiation + checkpoint inhibitors, Local chemotherapy + checkpoint inhibitors and Checkpoint agonists for Neuro-Inflammation., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Glioblastoma multiforme (GBM), is a frequent class of malignant brain tumors. Epigenetic therapy, especially with synergistic combinations is highly paid attention for aggressive solid tumors like GBM. Here, RSM optimization has been used to increase the efficient arrest of U87 and U251 cell lines due to synergistic effects. Cell lines were treated with SAHA, 5-Azacytidine, GSK-126, and PTC-209 individually and then RSM was used to find most effective combinations. Results showed that optimized combinations significantly reduce cell survival and induce cell cycle arrest and apoptosis in both cell lines. Expression of cyclin B1 and cyclin D1 were decreased while caspase3 increased expression.

Introduction: Hypoxia-induced autophagy leads to an increase in vasculogenic-mimicry (VM) and the development of resistance of glioblastoma-cells to bevacizumab (BEV). Chloroquine (HCQ) inhibits autophagy, reduces VM and can thus produce a synergistic effect in anti-angiogenic-therapy by delaying the development of resistance to BEV., Purpose: We retrospectively compared the combined addition of HCQ+BEV and adjuvant-radiochemotherapy (aRCT) to aRCT alone for recurrent-glioblastoma (rGBM) in regards of overall survival (OS)., Methods: Between 2006 and 2016, 134 patients underwent neurosurgery for rGBM at our institution. Forty-two patients (Karnofsky-Performance-Score>60%) with primary-glioblastoma underwent repeat-surgery and aRCT for recurrence. Four patients (9.5%) received aRCT+HCQ+BEV. Five patients received aRCT+BEV., Results: In rGBM-patients who were treated with aRCT+HCQ+BEV, median OS was 36.57 months and median post-recurrence-survival (PRS) was 23.92 months while median PRS in the control-group was 9.63 months ( p =0.022). In patients who received aRCT+BEV, OS and PRS were 26.83 and 12.97 months, respectively., Conclusions: Although this study was performed on a small number of highly selected patients, it demonstrates a synergistic effect of HCQ+BEV in the treatment of rGBM which previously could be demonstrated based on experimental data. A significant increase of OS in patients who receive aRCT+HCQ+BEV cannot be ruled out and should be further investigated in randomised-controlled-trials.

Glioblastoma (GBM) is an aggressive malignant type of brain tumor. Targeting one single intracellular pathway might not alleviate the disease, rather it activates the other molecular pathways that lead to the worsening of the disease condition. Therefore, in this study, we attempted to target both isocitrate dehydrogenase 1 (IDH1) and IDH2, which are one of the most commonly mutated proteins in GBM and other cancer types. Here, standard precision and extra precision docking, IFD, MM-GBSA, QikProp, and molecular dynamics (MD) simulation were performed to identify the potential dual inhibitor for IDH1 and IDH2 from the enamine database containing 59,161 ligands. Upon docking the ligands with IDH1 (PDB: 6VEI) and IDH2 (PDB: 6VFZ), the top eight ligands were selected, based on the XP Glide score. These ligands produced favourable MMGBSA scores and ADME characteristics. Finally, the top four ligands 12953, 44825, 51295, and 53210 were subjected to MD analysis. Interestingly, 53210 showed maximum interaction with Gln 277 for 99% in IDH1 and Gln 316 for 100% in IDH2, which are the crucial amino acids for the inhibitory function of IDH1 and IDH2 to target GBM. Therefore, the present study attempts to identify the novel molecules which could possess a pan-inhibitory action on both IDH1 and IDH that could be crucial in the management of GBM. Yet further evaluation involving in vitro and in vivo studies is warranted to support the data in our current study.Communicated by Ramaswamy H. Sarma.

Glioblastoma, the most severe form of brain tumor and a leading cause of death within a year of diagnosis, is characterized by excessive protein synthesis and folding in the lumen of the endoplasmic reticulum (ER), leading to increased ER stress in the cells of GBM tissues. To mitigate this stress the cancer cells have intelligently adopted a plethora of response mechanisms and Unfolded Protein Response (UPR) is one of those. To bear with this exhaustive situation cells upregulate a strong protein degradation system in form of 26S proteasome and blocking of proteasomal gene synthesis may be a potential therapeutic action against GBM. Proteasomal gene synthesis is exclusively dependent on the transcription factor Nuclear respiratory factor 1 (NRF1) and its activating enzyme DNA damage inducible 1 homolog 2 (DDI2). Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.

Glioblastoma multiforme (GBM), the most aggressive primary malignant brain tumor, is resistant to conventional radiotherapies and chemotherapies, including temozolomide (TMZ). Overcoming GBM resistance to the chemotherapeutic agent TMZ poses an important therapeutic problem. This study established an association between the long noncoding RNA TP73-AS1 and TMZ sensitivity regulation in human GBM cells (U87MG). Transcriptomic analysis revealed that TP73-AS1 expression was reduced in TMZ-resistant U87MG RT100 cells compared to that in parental U87MG cells. Additionally, TP73-AS1 knockdown in parental U87MG cells decreased their sensitivity to TMZ. Overall, these findings suggest that TP73-AS1 functions as a regulator of TMZ sensitivity in GBM cells.

Glioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14-22 months. Standard treatment of GBM includes maximum safe resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ), given over a period of approximately 9 months. Treatment and follow-up for Greenlandic patients with GBM are managed at Rigshospitalet (RH), Copenhagen. Greenlandic GBM patients, therefore, travel back and forth to RH, often unaccompanied, and challenged by cognitive failure or other symptoms from their disease and/or treatment. Few Greenlandic patients are diagnosed with GBM annually, but considering the poor prognosis and short remaining lifespan, it would be preferable to limit their travels. TMZ is administrated as capsules. Health personnel at Queen Ingrid's Hospital (DIH), Nuuk, are trained in treating other oncological diseases and handling side effects. Hence, it could be investigated whether administration of adjuvant TMZ at DIH could be feasible after personnel education as well as economic consideration and compensation, in close collaboration with neuro oncologists at RH. In this article, we describe the Greenlandic cancer treatment, and the typical workflow from diagnosis of GBM to treatment to progression.

Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of 'platelets with ultrasound-triggered release property', which takes advantage of 1) the platelets' ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM.

Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/autophagy as a key component of its anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of MTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma. Abbreviations: ATG: autophagy related; BAFA1: bafilomycin A 1 ; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.

Objectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling 'mitocans' such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues. Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX). Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A. Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

Sensitizing strategy is required to improve the clinical management of glioblastoma (GBM). 5-Lipoxygenase (Alox5) has been recently garnered attention due to its pro-carcinogenic roles in various cancers. This study demonstrates that Alox5 is overexpressed in GBM but not normal neuronal tissues. Alox5 depletion inhibits the growth of GBM cells, both in bulky and stem-like populations, and enhances the anti-cancer effects of temozolomide. The mechanism behind this involves a decrease in β-catenin level and activity upon Alox5 depletion. The inhibitory effects of Alox5 can be reversed by the addition of a Wnt agonist. Additionally, the study reveals that zileuton, an Alox5 inhibitor approved for asthma treatment, significantly improves the efficacy of temozolomide in mice without causing toxicity. Combination index analysis clearly demonstrates that zileuton and temozolomide act synergistically. These findings highlight the importance of Alox5 as a critical regulator of glioblastoma sensitivity and suggest the potential repurposing of zileuton for GBM treatment.

Introduction: Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the experience with ADCs in brain tumors and examines future paths for their use in these tumors., Areas Covered: This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors., Expert Opinion: ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.

Macroautophagy/autophagy, a stress-responsive cellular survival mechanism, plays important and context-dependent roles in cancer, and its inhibition has been implicated as a promising cancer therapeutic approach. The detailed mechanisms underlying the function of autophagy in cancer have not been fully understood. In this study, we show that autophagy inhibition promotes both the efficacy of chemotherapy for the treatment of glioblastoma (GBM) and therapy-induced senescence of GBM cells. As a specific cell fate characterized by permanent cell cycle arrest, senescence is also associated with the expression of a panel of specific secreted protein factors known as senescence-associated secretory phenotype (SASP). Intriguingly, we found that autophagy inhibition not only quantitatively enhanced GBM cell senescence but also qualitatively altered the spectrum of SASP. The altered SASP had increased potent activity to induce paracrine senescence of neighboring GBM cells, to skew macrophage polarization toward the anti-tumor M1 state, and to block the recruitment of pro-tumor neutrophils to GBM tumor tissues. Taken together, this study reveals novel functional communication between autophagy and senescence and suggests cancer therapeutic approaches harnessing autophagy blockage in inducing senescence-mediated antitumor immunity.

Introduction: Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches., Areas Covered: This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations., Expert Opinion: GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific 'off-the-shelf' CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.

Recent evidence has implicated microRNA-219 (miR-219) in regulation of gene contributed in glioblastoma (GBM) pathogenesis. This study aimed to prepare miR-219 in chitosan (CS) nanoparticles (NPs), characterize and investigate their efficacy on human GBM cell line (U87 MG). NPs were prepared using ionic gelation method. The influence of process parameters on physicochemical characteristics of NPs was investigated. Apoptotic effect of miR-219 was examined on U87 MG cells. Formulated NPs showed particle size of 109 ± 2.18 nm, with poly dispersity index equal to 0.2 ± 0.05, and zeta potential of +20.5 ± 0.7 mV. Entrapment efficiency of miR-219 in loaded NP has reached 95%. The in vitro release study demonstrated sustained release pattern of miR-219 from CS-NPs. Gel retardation assay has confirmed the integrity of miR-219 after production process. The fabricated NPs reduced the survival of U87 MG cells to 78% after 24 h of post-transfection, and into 67.5% after 48 h. However, fibroblasts were not affected by the NPs, revealing their specificity for GBM cells. Given the tumour suppressing function of miR-219, and advantage of CS-NPs for gene delivery to the central nervous system, the presented NPs have a great potential for treatment of GBM.

Despite surgical and therapeutic advances, glioblastoma multiforme (GBM) is among the most fatal primary brain tumor that is aggressive in nature. Patients with GBM have a median lifespan of just 15 months when treated with the current standard of therapy, which includes surgical resection and concomitant chemo-radiotherapy. In recent years, nanotechnology has shown considerable promise in treating a variety of illnesses, and certain nanomaterials have been proven to pass the blood-brain barrier (BBB) and stay in glioblastoma tissues. Recent preclinical research suggests that the diagnosis and treatment of brain tumor is significantly explored through the intervention of nanomaterials that has showed enhanced effect. In order to elicit an antitumor response, it is necessary to retain the therapeutic candidates within glioblastoma tissues and this job is effectively carried out by nanocarrier particularly functionalized nanocarriers. In the arena of neoplastic diseases including GBM have achieved great attention in recent decades. Furthermore, interleukin-13 receptor α chain variant 2 (IL13Rα2) is a highly expressed and studied target in GBM that is lacked by the surrounding environment. The absence of IL13Rα2 in surrounding normal tissues has made it a suitable target in glioblastoma therapy. In this review article, we highlighted the role of IL13Rα2 as a potential target in GBM along with design and fabrication of efficient targeting strategies for IL13Rα2 through surface functionalized nanocarriers.

Among the chemotypes studied for selective inhibition of tumour-associated carbonic anhydrases (CAs), SLC-0111 , a ureido-bearing benzenesulfonamide CA IX inhibitor, displayed promising antiproliferative effects in cancer cells in vitro and in vivo , being in Phase Ib/II clinical development. To explore the structural characteristics required for better discrimination of less conserved regions of the enzyme, we investigate the incorporation of the urea linker into an imidazolidin-2-one cycle, a modification already explored previously for obtaining CA inhibitors. This new library of compounds inhibited potently four different hCAs in the nanomolar range with a different isoform selectivity profile compared to the lead SLC-0111 . Several representative CA IX inhibitors were tested for their efficacy to inhibit the proliferation of glioblastoma, pancreatic, and breast cancer cells expressing CA IX, in hypoxic conditions. Unlike previous literature data on SLC-149 , a structurally related sulphonamide to compounds investigated here, our data reveal that these derivatives possess promising anti-proliferative effects, comparable to those of SLC-0111 .

Glioblastoma is rather recalcitrant to existing therapies and effective interventions are needed. Here we report a novel microenvironment-responsive micellar system (ch-K5(s-s)R8-An) for the co-delivery of the radiosensitizer Dbait and the chemotherapeutic doxorubicin (DOX) to glioblastoma. Accordingly, the ch-K5(s-s)R8-An/(Dbait-DOX) micelles plus radiotherapy (RT) treatment resulted in a high degree of apoptosis and DNA damage, which significantly reduced cell viability and proliferation capacity of U251 cells to 64.0% and 16.3%, respectively. The angiopep-2-modified micelles exhibited substantial accumulation in brain-localized U251 glioblastoma xenografts in mice compared to angiopep-2-lacking micelles. The ch-K5(s-s)R8-An/(Dbait-DOX) + RT treatment group exhibited the smallest tumor size and most profound tumor tissue injury in orthotopic U251 tumors, leading to an increase in median survival time of U251 tumor-bearing mice from 26 days to 56 days. The ch-K5(s-s)R8-An/(Dbait-DOX) micelles can be targeted to brain-localized U251 tumor xenografts and sensitize the tumor to chemotherapy and radiotherapy, thereby overcoming the inherent therapeutic challenges associated with malignant glioblastoma.

Temozolomide (TMZ) is the primary chemotherapeutic drug for treating glioblastoma (GBM); however, the final clinical outcome is considerably limited by the poor response and resistance to TMZ. Although autophagy is thought to be associated with chemotherapy resistance and cancer cell survival, the precise molecular mechanisms underlying this process remain elusive. The suppressor of cytokine signaling (SOCS) family is widely distributed in vivo and exerts a range of effects on tumors; however, the expression pattern and role of SOCS in GBM remains unknown. In this study, we determined that high SOCS5 expression level was associated with poor prognosis and TMZ resistance in GBM. TMZ induced an increase in SOCS5 expression level and upregulated autophagy during the acquisition of drug resistance. The observed increase in the extent of autophagy was mediated by SOCS5. Mechanistically, SOCS5 enhances the transcription of Bcl-2. Knockdown of SOCS5 inhibited TMZ chemoresistance in GBM cells through the inhibition of Bcl-2 recruited autophagy; upregulation of Bcl-2 blocked this effect. In summary, our findings revealed the involvement and underlying mechanism of SOCS5 in TMZ resistance. SOCS5 plays a critical role in GBM chemoresistance and may serve as a novel prognostic marker and therapeutic target for chemotherapeutically treating drug-resistant GBM.

p -Coumaric acid (pCA) is a hydroxycinnamic acid derivative commonly found in many natural products that has been extensively studied for its anticancer activity in multiple cell lines. In this report we investigated the effects of this phytochemical as adjuvant therapy to treat glioblastoma, an infaust brain tumour characterized by the acquired or innate resistance to the conventional chemotherapy temozolomide (TMZ). U87Mg glioblastoma cell growth and viability was assessed by growth rate curves and MTT assay incubating cells with 0.5 and 1 mM pCA for 24 h, 48 h and 72 h. Cell cycle analysis, performed by flow cytometry, showed that pCA led the accumulation of GBM cells in G2/M phase. Western blot analysis shows that pCA induced CDK4 cyclin-dependent kinase reduction and p53 increase, followed by induction of the CDK inhibitor p21. Furthermore, pCA treatment mediated the activation of apoptosis and the inhibition of migration of U87Mg cells. Finally, the treatment of glioblastoma cells in vitro with pCA concomitantly with the TMZ revealed a synergistic effect between the natural substance and the chemotherapy. In conclusion, our results demonstrated that pCA acts influencing the cell viability and cell cycle of U87Mg cells by promoting cell cycle arrest in G2/M phase and apoptosis.

Although temozolomide (TMZ) is recommended for glioblastoma (GBM) treatment, patients treated with TMZ usually develop TMZ resistance. Thus, there is an urgent need to elucidate the mechanism through which GBM cells acquire TMZ resistance. FOXD3-AS1, a recently discovered lncRNA, shows high expression in diverse cancer types. Nonetheless, its role in GBM remains unclear. This study found that FOXD3-AS1 was overexpressed in GBM cells and associated with dismal prognostic outcome in GBM patients. Functional studies revealed that depletion of FOXD3-AS1 inhibited cell growth and induced apoptosis of GBM cells. Results also showed that FOXD3-AS1 participates in the tolerance of GBM cells to TMZ. Specifically, TMZ-resistant cells exhibited higher FOXD3-AS1 expression compared to parental cells. Overexpression of FOXD3-AS1 increased TMZ tolerance in TMZ sensitive cells, whereas depletion of FOXD3-AS1 sensitized TMZ-resistant cells to TMZ treatment. Mechanistically, WEE1 was positively expressed with FOXD3-AS1. Given that both FOXD3-AS1 and WEE1 contain a binding site for miR-128-3p, FOXD3-AS1 could act as a competing endogenous RNA (ceRNA) to promote WEE1 expression by sponging miR-128-3p. Furthermore, we demonstrated that WEE1 was upregulated in TMZ-resistant GBM cells. Overexpression of WEE1 increased TMZ tolerance in TMZ sensitive cells, whereas deletion of FOXD3-AS1 promoted TMZ-resistant cells to be more sensitive to TMZ. Importantly, depletion of WEE1 could reverse TMZ resistant phenotype in FOXD3-AS1-overexpressed GBM cells. Collectively, our findings reveal a critical role of FOXD3-AS1 in the survival of GBM cells and TMZ resistance, which suggests that FOXD3-AS1 is a potential biomarker for the diagnosis and treatment of GBM.

Background: Previous studies had reported on the cytotoxic activities of generic antibiotics such as doxycycline (DOXY) and azithromycin (AZI) in multiple types of human cancers. Given that resistance to standard anti-glioblastoma multiforme (GBM) drug [temozolomide (TMZ)] is common and inevitable, alternative candidates are greatly needed., Purpose and Method: The present study was undertaken to explore the cytotoxicity and anticancer effects of DOXY and AZI on human GBM U87 cells via 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), Hoechst, Annexin V-FITC/PI, and clonogenic assays. CompuSyn software was used to determine the combination index (CI) for DOXY+AZI., Result: Individual treatment with DOXY and AZI decreased U87 cell viability in dose- and time-dependent, and quantitatively comparable to TMZ. Nevertheless, combinations of both antibiotics evidenced antagonistic behaviour in U87 cells. Increased apoptotic event was also observed with the individual treatment of DOXY and AZI. Furthermore, the proliferative and clonogenic capability of 21-day survived U87 cells was completely terminated by DOXY and AZI, but not TMZ., Conclusion: The antiproliferative and apoptosis-inducing activity exhibited by both antibiotics against U87 cells demonstrates their potential as a likely alternative to combat GBM. It would be interesting to find out more about their molecular players and cytotoxic effects in different types of GBM cells, including glioma stem cells (GSCs).

Novel 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues ( 7a-l ) were developed by the Cu alkyne-azide cycloaddition (CuAAC) reaction. The obtained lead compounds were confirmed by using 1 H NMR, 13 C NMR, 2 D NMR, HRMS and their anticancer activities were screened against Huh-7 liver cancer cells and U87MG human glioblastoma cells. Among the synthesized fluorinated 1,2,3-triazolyl nucleosides, three compounds ( 7i, 7a-b ) demonstrated promising anti-proliferative against Huh-7 and U87MG cell lines. Significantly, compound 7i has displayed remarkable promising anticancer activity with IC 50 value in the micromole range (22.41-24.92 µM) and (18.12-21.36 µM) against Huh-7 cancer cells and U87MG glioblastoma cells, respectively.

Nop2/Sun RNA methyltransferase (NSUN6) is an RNA 5-methyl cytosine (5mC) transferase with little information known of its function in cancer and response to cancer therapy. Here, we show that NSUN6 methylates both large and small RNA in glioblastoma and controls glioblastoma response to temozolomide with or without influence of the MGMT promoter status, with high NSUN6 expression conferring survival benefit to glioblastoma patients and in other cancers. Mechanistically, our results show that NSUN6 controls response to TMZ therapy via 5mC-mediated regulation of NELFB and RPS6BK2. Taken together, we present evidence that show that NSUN6-mediated 5mC deposition regulates transcriptional pause by accumulation of NELFB and the general transcription factor complexes (POLR2A, TBP, TFIIA, and TFIIE) on the preinitiation complex at the TATA binding site to control translation machinery in glioblastoma response to alkylating agents. Our findings open a new frontier into controlling of transcriptional regulation by RNA methyltransferase and 5mC.

Cisplatin (CDDP) has been widely used for glioblastoma treatment. miR-485-5p and E2F transcription factor 1 (E2F1) dysfunction has been reported in glioblastoma. Nonetheless, whether CDDP affects glioblastoma progression via the miR-485-5p-E2F1 axis requires investigation. The expression of miR-485-5p and E2F1 was investigated by quantitative real-time polymerase chain reaction or western blotting in glioblastoma tissues and cell lines. The interaction between miR-485-5p and E2F1 was confirmed using a luciferase assay. The malignancy of glioblastoma was detected using Cell Counting Kit-8, bromodeoxyuridine (BrdU), cell adhesion, flow cytometry, and transwell assays. We identified miR-485-5p downregulation and E2F1 upregulation in glioblastoma, and miR-485-5p inhibited cell growth and elevated cell apoptosis in glioblastoma cells after CDDP treatment. Moreover, miR-485-5p targeting E2F1 repressed cell growth and improved cell apoptosis in glioblastoma cells after CDDP treatment. Our study revealed that CDDP retarded glioblastoma cell development via the miR-485-5p-E2F1 axis, which may be a new direction for glioblastoma therapy.

Glioblastoma (GBM) is the most common malignant primary brain tumor, and GBM patients have a poor overall prognosis. CDC20 expression is increased in a variety of tumors and associated with temozolomide (TMZ) resistance in glioma cells. Apcin specifically binds to CDC20 to inhibit APC/C-CDC20 interaction and exhibits antitumor properties. The purpose of this article was to assess whether apcin inhibits tumor growth in glioma cell lines and increases the sensitivity of GBM to TMZ. In this study, a series of biochemical assays, such as Cell Counting Kit-8 (CCK-8), wound healing, apoptosis and colony formation assays, were performed to determine the antitumor properties of apcin in glioma cells. GBM cell apoptosis was detected by western blotting analysis of related proteins. Apcin increased the sensitivity of glioma to TMZ, as confirmed by CCK-8 and western blotting analysis. The results showed that apcin significantly inhibited the proliferation of glioma cells in a time- and dose-dependent manner. The migration decreased with increasing apcin concentrations. Increased Bim expression indicated that apcin promotes the apoptosis of glioma cells. Furthermore, apcin improved glioma sensitivity to TMZ. The results showed that apcin can effectively inhibit GBM growth and improve TMZ sensitivity. Apcin has the potential to treat GBM and is expected to provide new ideas for individualized treatment.

Glioblastoma multiform (GBM) is the most frequent type of malignant brain tumor with a poor prognosis. After optimal surgery, radiotherapy plus temozolomide (TMZ) is the standard treatment for GBM patients. However, the development of TMZ resistance limits its efficacy in GBM management. Runt Related Transcription Factor 1 (RUNX1) and microRNAs have been implicated in drug resistance of TMZ in GBM. In this study, we revealed the underlying mechanism of TMZ resistance and identified miR-128-3p/RUNX1 axis as a novel target for TMZ resistance in GBM. RUNX1 expression was significantly upregulated in GBM tissues as compared to normal tissues, and its expression was even higher in recurrent GBM tissues and TMZ-resistant GBM cells. RUNX1 depletion inhibited the viability, proliferation, migration, invasion and TMZ resistance of GBM cells, which could be rescued by RUNX1 overexpression. We further identified miR-128-3p as a tumor-suppressor whose overexpression restored the sensitivity of TMZ in GBM cells. miR-128-3p negatively regulated RUNX1 and subsequently downregulated multidrug resistance-associated protein 1 (MRP1). Together, the present study indicates that RUNX1 confers TMZ resistance in GBM by upregulating MRP1, which is negatively regulated by miR-128-3p. Targeting miR-128-3p/RUNX1/MRP1 axis provides a potential strategy to overcome TMZ resistance in GBM.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d , 1e , 1q , 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.

Increasing evidence suggests that induction of lethal macroautophagy/autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of previous work, we demonstrate that pimozide and loperamide trigger an ATG5- and ATG7 (autophagy related 5 and 7)-dependent type of cell death that is significantly reduced with cathepsin inhibitors and the lipid reactive oxygen species (ROS) scavenger α-tocopherol in MZ-54 GBM cells. Global proteomic analysis after treatment with both drugs also revealed an increase of proteins related to lipid and cholesterol metabolic processes. These changes were accompanied by a massive accumulation of cholesterol and other lipids in the lysosomal compartment, indicative of impaired lipid transport/degradation. In line with these observations, pimozide and loperamide treatment were associated with a pronounced increase of bioactive sphingolipids including ceramides, glucosylceramides and sphingoid bases measured by targeted lipidomic analysis. Furthermore, pimozide and loperamide inhibited the activity of SMPD1/ASM (sphingomyelin phosphodiesterase 1) and promoted induction of lysosomal membrane permeabilization (LMP), as well as release of CTSB (cathepsin B) into the cytosol in MZ-54 wild-type (WT) cells. Whereas LMP and cell death were significantly attenuated in ATG5 and ATG7 knockout (KO) cells, both events were enhanced by depletion of the lysophagy receptor VCP (valosin containing protein), supporting a pro-survival function of lysophagy under these conditions. Collectively, our data suggest that pimozide and loperamide-driven autophagy and lipotoxicity synergize to induce LMP and cell death. The results also support the notion that simultaneous overactivation of autophagy and induction of LMP represents a promising approach for the treatment of GBM. Abbreviations : ACD: autophagic cell death; AKT1: AKT serine/threonine kinase 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; CERS1: ceramide synthase 1; CTSB: cathepsin B; CYBB/NOX2: cytochrome b-245 beta chain; ER: endoplasmatic reticulum; FBS: fetal bovine serum; GBM: glioblastoma; GO: gene ontology; HTR7/5-HT7: 5-hydroxytryptamine receptor 7; KD: knockdown; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAP: LC3-associated phagocytosis; LMP: lysosomal membrane permeabilization; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; RB1CC1: RB1 inducible coiled-coil 1; ROS: reactive oxygen species; RPS6: ribosomal protein S6; SMPD1/ASM: sphingomyelin phosphodiesterase 1; VCP/p97: valosin containing protein; WT: wild-type.

T cell-engaging therapies involving bispecific T cell engager (BiTE) and chimeric antigen receptor T (CAR-T) cells have achieved great success in the treatment of hematological tumors. However, the paucity of ideal cell surface molecules that can be targeted on glioblastoma (GBM) partially reduces the immunotherapeutic efficacy. Recently, high expression of Fn14 has been reported in several solid tumors, so the strategy of exploiting this specific antigen for GBM immunotherapy is worth studying. Consequently, we constructed Fn14× CD3 BiTE and Fn14-specific CAR-T cells and investigated their cytotoxic activity against GBM in vitro and in vivo. First, expression of Fn14 was confirmed in glioma tissues and GBM cells. Then, we designed Fn14-specific BiTE and CAR-T cells and tested their cytotoxicity in GBM cell cultures and mouse models of GBM. Fn14 was highly expressed in GBM tissues and cell lines, while it was undetectable in normal brain samples. Fn14× CD3 BiTE, Fn14 CAR-T cells and Fn14 CAR-T/IL-15 cells were antigen-specific and highly cytotoxic, showing good antitumor activity in vitro and causing significant regression of established solid tumors in xenograft models. However, the xenografts treated with Fn14 CAR-T cells regrew, whereas xenografts treated with Fn14 CAR-T/IL-15 cells did not. IL-15 engineering augmented the antitumor activity of Fn14 CAR-T cells and resulted in significant antitumor effects similar to those of Fn14× CD3 BiTE. Our results suggest that Fn14 is an appropriate target for GBM. Anti-Fn14 BiTE and Fn14-specific CAR-T/IL-15 cells may be exciting immunotherapeutic options for malignant brain cancer., Competing Interests: The authors report no conflict of interest., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Glioblastoma (GB) is the most lethal form of primary brain neoplasm. TMZ is the first-line standard treatment, but the strong resistance constrains the efficacy in clinical use. GB contains glioma stem cells (GSCs), which contribute to TMZ resistance, promote cell survival evolvement, and repopulate the tumor mass. This review summarizes the TMZ-resistance mechanisms and discusses several potential therapies from the conservative opinion of GSC-targeted therapy orientation to the current view of TMZ resistance-aimed efficacy, which will provide an understanding of the role of heterogeneity in drug resistance and improve therapeutic efficacy in general.

Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumour prevalent in humans, that exhibits aggressive cell proliferation and rapid invasion of normal brain tissue. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection followed by radio-chemotherapy with temozolomide (TMZ), more than 95% of GBM patients die within 5 years after diagnosis. In most cases, the therapy is not able to counteract the growth and invasiveness of the tumour, which relapses after an interval of time that varies from patient to patient. An increasing number of evidence indicates that natural substances exhibited effective anti-tumour functions and might be successfully used in the treatment of GBM. This review summarizes some natural substances: lactoferrin, hispolon, aloe-emodin and tea tree oil; all these show a growth inhibition and synergistic effect when together with TMZ, (the most commonly used alkylating drug for the treatment of glioblastoma) were administered to U87MG glioblastoma cell line in vitro and in murine animal model. U87MG cell growth was monitored by daily cell count after treatments with the substances mentioned above and growth analysis showed that all drugs significantly decrease proliferation of U87MG in a time- and dose-dependent manner. FACS analysis demonstrates a block of cell cycle in S, G2/M or G0/G1 phases. These substances mediate multiple processes including apoptosis by releasing the inducing factor: PARP. Natural compounds, in combination with conventional chemotherapy TMZ, are a powerful approach to improve the effectiveness of brain cancer treatment.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone ( P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ ( P < .0001) and CD8+ IFN-γ ( P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain ( P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy., Competing Interests: The authors do not have any relevant conflicts of interest associated with this manuscript., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Introduction: Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure., Methods: Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays., Results: Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 ( P = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment., Conclusions: Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects., Competing Interests: This is for Dr. Michael Lim, the all other authors do not have conflicts of interest. Research Support: Arbor, BMS, Accuray, Tocagen, Biohaven, Kyrin-Kyowa, Biohaven Consultant: Tocagen, VBI, InCephalo Therapeutics, Pyramid Bio, Merck, BMS, Insightec, Biohaven, Sanianoia, Hemispherian, Black Diamond Therapeutics Shareholder – Egret Therapeutics Patent: Focused radiation + checkpoint inhibitors Local chemotherapy + checkpoint inhibitors Checkpoints for Neuro-Inflammation Non-research: Consultant - Stryker, (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1 WT ) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as β-catenin gene, pivotal for Wnt/β-catenin signaling, were upregulated in 206 IDH1 WT glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of β-catenin protein were further verified in IDH1 WT GBM patients and IDH1 WT GL261 glioma allografts. Subsequently, we found that IDH1 WT GL261 cell-derived conditioned medium activated Wnt/β-catenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/β-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1 WT GBM allografts by simultaneously enhancing cytotoxic CD8 + T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1 WT GBM allografts after the blockade of Wnt signaling. Finally, gavage administration of a Wnt signaling inhibitor significantly restrained tumor proliferation and improved the survival of model mice bearing IDH1 WT GBM allografts. Depletion of CD8 + T cells remarkably abrogated the therapeutic efficacy induced by the Wnt signaling inhibitor. Overall, the present work indicates that the crosstalk between IDH1 WT glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/β-catenin signaling is a promising complement for IDH1 WT GBM treatment by improving the hostile immunosuppressive microenvironment., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Glioblastomas (GBM) are heterogeneous highly vascular brain tumors exploiting the unique microenvironment in the brain to resist treatment and anti-tumor responses. Anti-angiogenic agents, immunotherapy, and targeted therapy have been studied extensively in GBM patients over a number of decades with minimal success. Despite maximal efforts, prognosis remains dismal with an overall survival of approximately 15 months.Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, underwent accelerated approval by the U.S. Food and Drug Administration in 2009 for the treatment of recurrent GBM based on promising preclinical and early clinical studies. Unfortunately, subsequent clinical trials did not find overall survival benefit. Pursuing pleiotropic targets and leaning toward multitarget strategies may be a key to more effective therapeutic intervention in GBM, but preclinical evaluation requires careful consideration of model choices. In this study, we discuss bevacizumab resistance, dual targeting of pro-angiogenic modulators VEGF and YKL-40 in the context of brain tumor microenvironment, and how model choice impacts study conclusions and its translational significance.

Glioblastoma (GBM) is the most aggressive and lethal neoplasia of the central nervous system in adults. Based on the molecular signature genes, GBM has been classified in proneural, neural, mesenchymal and classical subtypes. The Metallophosphoesterase-domain-containing protein 2 ( MPPED2 ) gene encodes a metallophosphodiesterase protein highly conserved throughout the evolution. MPPED2 downregulation, likely due to its promoter hypermethylation, has been found in several malignant neoplasias and correlated with a poor prognosis. In this study, we aimed to investigate the expression and the functional role of MPPED2 in GBM. TCGA and Gravendeel databases were employed to explore the MPPED2 expression levels in this type of tumor. We have found that MPPED2 expression is downregulated in GBM patients, showing a positive correlation with survival. Moreover, TCGA and Gravendeel data also revealed that MPPED2 expression negatively correlates with the most aggressive mesenchymal subtype. Additionally, the restoration of MPPED2 expression in U251 and GLI36 GBM cell lines decreases cell growth, migration and enhanced the sensitivity to the temozolomide, inducing apoptotic cell death, of GBM cells. These findings suggest that the restoration of MPPED2 function can be taken into consideration for an innovative GBM therapy.

Multimodality 3D Optical Imaging (OI)/CT has the potential to play a major role in drug development for glioblastomas (GBM), as it is an accessible preclinical method. To demonstrate the potential of 3D OI/CT to visualize orthotopic GBM implantation, we labeled GBM cells with Cy7 and imaged their location using 3D OI/CT. To confirm the accuracy of the spatial localization and demonstrate the ability to image locoregionally delivered therapies, we labeled mouse albumin with Cy7 (Cy7ALB) and delivered it via locoregional infusion 1 mm or 3 mm into the brain and demonstrated correlation of signal between the 3D OI/CT and post necropsy brain slices. In addition, we demonstrated the potential of systemically delivered Cy7ALB contrast to detect blood-brain barrier (BBB) permeability caused by orthotopic GBMs using 3D OI/CT. We also tested the potential of 3D OI/CT to assess focal BBB permeability induced by high intensity focused ultrasound (HIFU), a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. We demonstrated the ability of systemic Cy7ALB contrast together with 3D OI/CT to accurately assess real-time HIFU-induced BBB permeability, which correlated to post necropsy imaging of brains. Furthermore, we demonstrated that 3D OI/CT can also image the therapeutic distribution of a Cy7-labeled anti-PD-1 antibody, a prototype translational antibody therapy. We successfully imaged real-time antibody distribution after HIFU-induced BBB permeability, which correlated with post necropsy Cy7 signal and translational PET imaging after injection of [ 89 Zr] anti-PD-1 antibody. Thus, we demonstrated the broad potential of using 3D OI/CT as an accessible preclinical tool to develop anti-GBM therapies.

Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM. Using the ilomastat Leu-Trp backbone, we have synthesised novel sulphonamides and monitored the performance of these compounds in conditioned media expressing MMP3. From the results discussed herein we demonstrate the performance of sulfonamide based MMPIs included AP-3, AP-6, and AP-7.

Introduction: Glioblastoma (GBM) is the most common primary malignant central nervous system tumor and has a poor overall outcome despite an aggressive standard-of-care treatment. Hence, better therapeutic modalities are necessary. Immunotherapy is a novel modality that has an indirect action against the tumor cells through activation of an anti-tumor immune response., Areas Covered: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) belongs to a class of molecules called immune checkpoints that are inherently expressed on immune cells and lead to attenuation of the immune response. Inhibition of such molecules has been approved for the treatment of melanoma, and prolonged survival and complete responses have been reported in preclinical GBM mouse models. Ipilimumab inhibits CTLA-4 and is being investigated for the treatment of GBM, alone or in combination with other treatment modalities, in various preclinical and clinical studies, the results of the most relevant of which are discussed in this review., Expert Opinion: Combining ipilimumab with other immunotherapy modalities and using it in specific conditions may increase the rate of objective responses in patients with GBM.

Background: Prior to 2000, the DNA alkylating agents nitrosoureas were used as standard treatment of glioblastoma. Current treatments for glioblastoma patients consist of surgery followed by radiation in combination with temozolomide. Despite therapeutic advances, the prognosis for glioblastoma patients remains grim, with a five-year overall survival below 15%. In this study, our team analyzed the interaction between temozolomide and doxorubicin in a glioblastoma cell line, in vitro ., Materials and Method: The cell line, established from a patient who underwent surgery at the "Bagdasar Arseni Emergency Hospital", was exposed to 10 µM and 100 µM of temozolomide and 10 nM and 100 nM of doxorubicin, respectively, over a period of 7, 10 and 14 days, in monotherapy and in combination., Results: The results showed that both temozolomide (66.5% cytotoxicity for the 10 µM dose at 14 days) de and doxorubicin (66.8% cytotoxicity for the 10 nM dose after 14 days) were very effective in killing cancer cells in monotherapy, but failed to produce a synergistic effect when used in combination., Conclusion: While the results may be discouraging, they present an interesting prospect into how certain drug interactions can impact treatment response.

Introduction: Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic options are therefore urgently needed; however, there have been various drug failures in late-stage clinical development. The proteasome represents a key target for anti-cancer therapy as successfully shown in multiple myeloma and other hematologic malignancies., Areas Covered: This review article summarizes the preclinical and clinical development of proteasome inhibitors in the context of glioblastoma., Expert Opinion: Early clinical trials with bortezomib ended with disappointing results, possibly because this agent does not cross the blood-brain barrier. In contrast to bortezomib and other proteasome inhibitors, marizomib is a novel drug that displays strong inhibitory properties on all enzymatic subunits of the proteasome and, most importantly, crosses the blood-brain barrier, making it a potentially very active novel agent against intrinsic brain tumors. While preclinical studies have demonstrated significant anti-glioma activity, its clinical benefit has yet to be proven. Exploiting the biological effects of proteasome inhibitors in combination with other therapeutic strategies may represent a key next step in their clinical development.

Glioblastoma multiforme (GBM, grade IV) is the most common malignant and invasive central nervous system tumor with poor survival outcome. Various pathogenesis signatures such as genetic mutation, hypoxia, necrosis and neo-angiogenesis are involved in GBM. Standard treatment includes surgical resection along with radiation therapy and temozolomide (TMZ) chemotherapy that do not improve the overall survival of patients. In this review, we focused on the diagnosis, risk factors and novel therapies, using advanced therapies such as nanotechnology in drug delivery, gene therapy and hyperthermia that have promising roles in the treatment of aggressive brain tumors.

Introduction : The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas. Areas covered : Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches. Expert opinion : Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials.