Glioma Therapy Research Articles

Functionalized nanoparticles crossing the brain-blood barrier to target glioma cells.

Glioma is the most common tumor of the central nervous system (CNS), with a 5-year survival rate of <35%. Drug therapy, such as chemotherapeutic and immunotherapeutic agents, remains one of the main treatment modalities for glioma, including temozolomide, doxorubicin, bortezomib, cabazitaxel, dihydroartemisinin, immune checkpoint inhibitors, as well as other approaches such as siRNA, ferroptosis induction, etc. However, the filter function of the blood-brain barrier (BBB) reduces the amount of drugs needed to effectively target CNS tumors, making it one of the main reasons for poor drug efficacies in glioma. Thus, finding a suitable drug delivery platform that can cross the BBB, increase drug aggregation and retainment in tumoral areas and avoid accumulation in non-targeted areas remains an unsolved challenge in glioma drug therapy. An ideal drug delivery system for glioma therapy should have the following features: (1) prolonged drug life in circulation and effective penetration through the BBB; (2) adequate accumulation within the tumor (3) controlled-drug release modulation; (4) good clearance from the body without significant toxicity and immunogenicity, etc. In this regard, due to their unique structural features, nanocarriers can effectively span the BBB and target glioma cells through surface functionalization, providing a new and effective strategy for drug delivery. In this article, we discuss the characteristics and pathways of different nanocarriers for crossing the BBB and targeting glioma by listing different materials for drug delivery platforms, including lipid materials, polymers, nanocrystals, inorganic nanomaterials, etc.

How Nanotherapeutic Platforms Play a Key Role in Glioma? A Comprehensive Review of Literature.

Glioblastoma (GBM), a highly aggressive form of brain cancer, is considered one of the deadliest cancers, and even with the most advanced medical treatments, most affected patients have a poor prognosis. However, recent advances in nanotechnology offer promising avenues for the development of versatile therapeutic and diagnostic nanoplatforms that can deliver drugs to brain tumor sites through the blood-brain barrier (BBB). Despite these breakthroughs, the use of nanoplatforms in GBM therapy has been a subject of great controversy due to concerns over the biosafety of these nanoplatforms. In recent years, biomimetic nanoplatforms have gained unprecedented attention in the biomedical field. With advantages such as extended circulation times, and improved immune evasion and active targeting compared to conventional nanosystems, bionanoparticles have shown great potential for use in biomedical applications. In this prospective article, we endeavor to comprehensively review the application of bionanomaterials in the treatment of glioma, focusing on the rational design of multifunctional nanoplatforms to facilitate BBB infiltration, promote efficient accumulation in the tumor, enable precise tumor imaging, and achieve remarkable tumor suppression. Furthermore, we discuss the challenges and future trends in this field. Through careful design and optimization of nanoplatforms, researchers are paving the way toward safer and more effective therapies for GBM patients. The development of biomimetic nanoplatform applications for glioma therapy is a promising avenue for precision medicine, which could ultimately improve patient outcomes and quality of life.

Targeted glioma therapy makes strides

Targeted glioma therapy makes strides

Non-invasive methods of molecular diagnosis, clinical monitoring and approaches to the personalized therapy of diffuse midline glioma

The purpose of the study was to summarize and analyze modern data about non-invasive methods of molecular diagnosis and approaches to the personalized therapy of diffuse midline glioma (DMG). Material and Methods. The search and analysis of publications was carried out using Google Scholar, Pubmed, Elsevier, Web of Science, Elibrary systems. The review includes publications published from 2011 to 2022. Of the 102 articles found, 59 were used to write the review. Results. In this review, we discuss the spectrum of somatic driver mutations present in DMG tumor cells and their relationship with the sensitivity of tumor cells to certain types of therapy - a pharmacogenetic approach to the selection of individual treatments (targeted therapy). We provide examples of new methods of targeted therapy for DMG, which are currently at the stage of preclinical laboratory development. Also, we discuss examples of the use of 3D cell cultures for the development of targeted therapies, including the use of perfusion systems. The review describes the methods of analysis of liquid biopsy, which allow the detection of tumor-specific biomarkers in the non-invasive diagnosis of DMG, including a number of methods that have not yet been tested in the clinic. The following is a list of tumor-specific biomarkers for diagnosing, monitoring, and selecting targeted therapy for DMG. Finally, we discuss the possibility of implementing these methods in the clinic and present the results of several clinical trials. Conclusion. In oncology, new methods of molecular genetics, such as analysis of liquid biopsy, allow diagnosis and monitoring of treatment in cases where classical methods that require tissue sampling are not applicable (for example, the analysis of genetically heterogeneous tumors and tumors of surgically inaccessible localization). These tumors include DMG, a primary brain tumor most common in children. The available data confirm the relevance of the search for new specific tumor biomarkers, as well as targets for targeted therapy of the paediatric-type diffuse gliomas.

Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics

BackgroundGlioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation.MethodsWe analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal.ResultsWe found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown.ConclusionOur study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.

HSPA4 regulated glioma progression via activation of AKT signaling pathway.

Glioma is still an incurable disease with high invasiveness. Heat shock 70kDa protein 4 (HSPA4) is a member of the HSP110 family, and is associated with the development and progression of various cancers. In the current study, we assessed the expression of HSPA4 in clinical samples, and found that HSPA4 was up-regulated in glioma tissues and correlated with tumor recurrence and grade. Survival analyses demonstrated that glioma patients with high HSPA4 expression had lower overall survival and disease-free survival times. In vitro knockdown of HSPA4 inhibited glioma cell proliferation, mediated cell cycle arrest at G2 phase and apoptosis, and reduced the migration ability. In vivo, the growth of HSPA4-knockdown xenografts was markedly suppressed compared to the tumors formed by HSPA4-positive control cells. Additionally, Gene set enrichment analyses disclosed that HSPA4 was associated with the PI3K/Akt signaling pathway. The regulatory effect of the AKT activator SC79 on cell proliferation and apoptosis was suppressed by HSPA4 knockdown, indicating that HSPA4 is capable of promoting glioma development. In summary, these data showed that HSPA4 is likely to play a pivotal role in the progression of glioma, and consequently may be a promising therapeutic target for glioma therapy.

Natural Products for the Immunotherapy of Glioma.

Glioma immunotherapy has attracted increasing attention since the immune system plays a vital role in suppressing tumor growth. Immunotherapy strategies are already being tested in clinical trials, such as immune checkpoint inhibitors (ICIs), vaccines, chimeric antigen receptor T-cell (CAR-T cell) therapy, and virus therapy. However, the clinical application of these immunotherapies is limited due to their tremendous side effects and slight efficacy caused by glioma heterogeneity, antigen escape, and the presence of glioma immunosuppressive microenvironment (GIME). Natural products have emerged as a promising and safe strategy for glioma therapy since most of them possess excellent antitumor effects and immunoregulatory properties by reversing GIME. This review summarizes the status of current immunotherapy strategies for glioma, including their obstacles. Then we discuss the recent advancement of natural products for glioma immunotherapy. Additionally, perspectives on the challenges and opportunities of natural compounds for modulating the glioma microenvironment are also illustrated.

Encapsulation of Au(III) Complex Using Lactoferrin Nanoparticles to Combat Glioma.

Metal-based drugs have been used for decades to treat solid cancers; however, these drugs have no significant therapeutic effect on glioma because they cannot effectively cross the blood-brain barrier (BBB). To develop a novel metal-based agent that can cross the BBB to target glioma, we synthesized an Au complex (C2) with remarkable glioma cytotoxicity and fabricated lactoferrin (LF)-C2 nanoparticles (LF-C2 NPs) as a novel therapy. We confirmed that C2 kills glioma cells by inducing apoptosis and autophagic death. The LF-C2 NPs cross the BBB, inhibit glioma growth, and selectively accumulate in the tumor tissue, significantly decreasing the side effects of C2. This study provides a novel strategy for applying metal-based agents to targeted therapy for glioma.

HGG-10. A SAFETY AND EFFICACY STUDY OF NOVOTTF-100A FOR PEDIATRIC HIGH-GRADE GLIOMA: RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE FIRST THREE CASES

Abstract BACKGROUND The safety and efficacy of Tumor-Treating Fields (TTFields) therapy for pediatric diffuse high-grade glioma (HGG) are uncertain. Despite differences between adult GBM and pediatric HGG in terms of genetic etiology, both have certain clinical behaviors in common, allowing TTFields therapy to be tested in pediatric HGG. METHODS The present study [jRCTs032200423] aims to evaluate the safety of NovoTTF-100A in pediatric HGG and conduct an exploratory analysis of its efficacy. The target population is ten children aged 5 to 17 years with newly diagnosed supratentorial HGG or its first-recurrence following frontline therapy. After completion of surgical resection of the tumor and radiation therapy, all the patients will receive TTFields therapy using NovoTTF-100A for 28 days per course for up to 26 courses until the end-of-therapy criteria (including disease progression) are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various efficacy parameters and quality of life. In total, the ten patients will be enrolled by September 2023. RESULTS The planned interim analysis, which was done in October 2022, included 3 female patients aged 14, 17, and 9 years, respectively. All had a histological grade 4 tumor, two of which were radiation-induced secondary HGG. Although the first patient with recurrent disease had early progression after enrollment and experienced disease-related adverse events, no serious, treatment-related toxicities or device-related issues were observed. The second patient had a recurrence after six courses, and the third patient remained through the second course. All 3 patients were able to maintain device usage of 75% or more of the time, in alignment with use recommendations, suggesting treatment feasibility. DISCUSSION Based on the results presented above, the study was resumed as the current, multicentric study aimed at obtaining approval for the expanded use of NovoTTF-100A for pediatric HGG.

HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS

Abstract PDGFRA is commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a fatal disease with no current options for cure. We performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations in ~15% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors regardless of genomic alteration. Tumors with PDGFRA gene amplification demonstrated significantly elevated PDGFRA expression in both H3K27M DMGs and H3 wild-type pHGGs relative to tumors with wild-type or point mutated PDGFRA. We tested a range of PDGFRA inhibitors against a panel of patient derived pediatric H3K27M DMG, pHGG, and adult HGG. Amongst the inhibitors tested, avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA showed potent toxicity against a wide array of pediatric and adult cell lines. This molecule also demonstrated supra-micromolar blood brain barrier penetration in pre-clinical in vivo models, and demonstrated significant decrease in tumor growth and improved survival in orthotopic mouse xenograft models. Finally, building on this preclinical activity, we report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib usage showed no significant acute toxicities within this patient cohort. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced promising clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in pediatric high grade glioma.

Biomimetic Nanocomposites Camouflaged with Hybrid Cell Membranes for Accurate Therapy of Early-Stage Glioma.

Glioma features high fatality rate and short survival time of patients due to its fast growth speed and high invasiveness, hence timely treatment of early-stage glioma is extremely important. However, the blood brain barrier (BBB) severely prevents therapeutic agents from entering the brain; meanwhile, the non-targeted distribution of agents always causes side effects to vulnerable cerebral tissues. Therefore, delivery systems that possess both BBB penetrability and precise glioma targeting ability are keenly desired. We herein proposed a hybrid cell membrane (HM) camouflage strategy to construct therapeutic nanocomposites, in which HM consisting of brain metastatic breast cancer cell membrane and glioma cell membrane was prepared with a simple membrane fusion pathway. By coating HM onto drug-loaded nanoparticles, the as-obtained biomimetic therapeutic agent (termed HMGINPs) inherited satisfying BBB penetrability and homologous glioma targeting ability simultaneously from the two source cells. HMGINPs exhibited good biocompatibility and superior therapeutic efficacy towards early-stage glioma.

Curcumin‐loaded nanoparticle based on poloxamer188 for glioma treatment: Synthesis, characterization and in vitro evaluation

AbstractGlioma is the most common primary cancer of central nervous system due to its rapid proliferation and high lethality. In this study, a novel poloxamer188‐based drug delivery system, poloxamer188‐poly(1,4,8‐trioxaspiro[4.6]undecan‐9‐one)‐poly(1,3‐dioxan‐2‐one) nanoparticles (P188TT NPs) were developed. The 1H NMR, Raman and FITC spectra demonstrated that P188TT copolymer was successfully synthesized. The critical micelle concentration (CMC) measurement showed that P188TT NPs had a low CMC. The characterization and bio‐safety assessment verified that P188TT NPs had the appropriate size, zeta potential, good stability, and ideal bio‐safety. In addition, the curcumin‐loaded P188TT NPs (Cur/P188TT NPs) were fabricated and then analyzed by differential scanning calorimeter (DSC) and thermalgravimetric analysis (TGA). The in vitro release study displayed that the release rate of Cur from Cur/P188TT NPs in pH 6.8 was appreciably faster than that in pH 7.4. The tissue distribution study showed that these NPs had good brain‐targeting efficiency. The cellular uptake assay suggested that P188TT NPs could promote the uptake of Cur in glioma cells. The MTT tests indicated that P188TT NPs could increase the anti‐tumor activity of encapsulated drugs. Therefore, P188TT NPs showed potential as a brain targeting nano‐carrier for glioma therapy, which required further validation in glioma models in vivo.

The value of basement membrane-associated genes in the prognosis and immune regulation of glioma.

Gliomas have a high incidence rate in central nervous tumors. Although many breakthroughs have been made in the pathogenesis and treatment of glioma, the recurrence and metastasis rates of patients have not been improved based on the uniqueness of glioma. Glioma destroys the surrounding basement membrane (BM), leading to local infiltration, resulting in the corresponding clinical and neurological symptoms. Therefore, exploring the biological roles played by BM associated genes in glioma is particularly necessary for a comprehensive understanding of the biological processes of glioma and its treatment. Differential expression and univariate COX regression analyses were used to identify the basement membrane genes (BMGs) to be included in the model. LASSO regression was used to construct the BMG model. The Kaplan-Meier (KM) survival analysis model was used to assess the prognosis discrimination between training sets, validation sets, and clinical subgroups. Receiver-operating characteristic (ROC) analysis was used to test the prognostic efficacy of the model. Use calibration curves to verify the accuracy of nomograms. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were used to analyze the function and pathway enrichment among the model groups. ESTIMATE and other 7 algorithms including CIBERSORT were used to evaluate the immune microenvironment. "pRRophetic" was used to evaluate drug sensitivity. This study demonstrated that high-risk genes (LAMB4, MMP1, MMP7) promote glioma progression and negatively correlate with patient prognosis. In the tumor microenvironment (TME), high-risk genes have increased scores of macrophages, neutrophils, immune checkpoints, chemokines, and chemokine receptors. This study suggests that BMGs, especially high-risk-related genes, are potential sites for glioma therapy, a new prospect for comprehensively understanding the molecular mechanism of glioma.

FOF1-ATPase Motor-Embedded Chromatophore as Drug Delivery System: Extraction, Cargo Loading Ability and Mucus Penetration Ability.

Mucosal drug delivery permits direct and prompt drug absorption, which is capable of reducing undesirable decomposition that occurs before absorption. However, mucus clearance of those mucosal drug delivery systems strongly retards their actual application. Herein, we propose chromatophore nanoparticles embedded with FOF1-ATPase motors to promote mucus penetration. The FOF1-ATPase motor-embedded chromatophores were firstly extracted from Thermus thermophilus by using a gradient centrifugation method. Then, the model drug (curcumin) was loaded onto the chromatophores. The drug loading efficiency and entrapment efficiency were optimized by using different loading approaches. The activity, motility, stability and mucus permeation of the drug-loaded chromatophore nanoparticles were thoroughly investigated. Both the in vitro and in vivo studies revealed that the FOF1-ATPase motor-embedded chromatophore successfully enhanced mucus penetration glioma therapy. This study indicates that the FOF1-ATPase motor-embedded chromatophore is a promising alternative as a mucosal drug delivery system.

Magnolol and Temozolomide exhibit a synergistic anti-glioma activity through MGMT inhibition

Temozolomide (TMZ) is the leading chemotherapeutic agent used for glioma therapy due to its good oral absorption and blood-brain barrier permeability. However, its anti-glioma efficacy may be limited due to its adverse effects and resistance development. O6-Methylguanine-DNA-methyltransferase (MGMT), an enzyme associated with TMZ resistance, is activated via the NF-κB pathway, which is found to be upregulated in glioma. TMZ also upregulates NF-κB signaling like many other alkylating agents. Magnolol (MGN), a natural anti-cancer agent, has been reported to inhibit NF-κB signaling in multiple myeloma, cholangiocarcinoma, and hepatocellular carcinoma. MGN has already shown promising results in anti-glioma therapy. However, the synergistic action of TMZ and MGN has not been explored. Therefore, we investigated the effect of TMZ and MGN treatment in glioma and observed their synergistic pro-apoptotic action in both in vitro and in vivo glioma models. To explore the mechanism of this synergistic action, we found that MGN inhibits MGMT enzyme both in vitro and in vivo glioma. Next, we established the link between NF-κB signaling and MGN-induced MGMT inhibition in glioma. MGN inhibits the phosphorylation of p65, a subunit of NF-κB, and its nuclear translocation to block NF-κB pathway activation in glioma. MGN-induced NF-κB inhibition results in the transcriptional inhibition of MGMT in glioma. TMZ and MGN combinatorial treatment also impedes p65 nuclear translocation to inhibit MGMT in glioma. We observed a similar effect of TMZ and MGN treatment in the rodent glioma model. Thus, we concluded that MGN potentiates TMZ-induced apoptosis in glioma by inhibiting NF-κB pathway-mediated MGMT activation.

The interplay of solvent-drug-protein interactions during albumin nanoparticles formulations for temozolomide delivery to brain cancer cells.

Temozolomide (TMZ), the first line for glioma therapy, suffers from stability at physiological pH. TMZ was selected as a challenging model drug for loading into human serum albumin nanoparticles (HSA NPs). Our aim is to optimise the conditions for TMZ loading into HSA NPs while ensuring TMZ stability. Blank and TMZ-HSA NPs were fabricated using the de-solvation technique and the effect of different formulation parameters was evaluated. For blank NPs, crosslinking time had no significant effect on NPs' size while acetone produced significantly smaller particles than ethanol. Upon drug loading, though TMZ was stable in acetone and ethanol as single agents yet, ethanol-based NPs showed misleadingly high EE% due to drug instability in ethanol formulations as evident by the UV spectrum.The optimum conditions for drug-loaded particles were: 10 mg/ml HSA, 4 mg TMZ using acetone, yielded NPs with 145 nm in diameter, ξ of -16.98 mV and 0.16% DL. The selected formula reduced the cell viabilities of GL261 glioblastoma cells and BL6 glioblastoma stem cells to 61.9% and 38.3%, respectively. Our results corroborated that careful manipulation of TMZ formulation processing parameters is crucial for encapsulating such chemically unstable dug while simultaneously ensuring its chemical stability.

Phase II trial evaluating nivolumab in patients with recurrent IDH-mutant gliomas with and without hypermutation phenotype.

e14043 Background: Tumor mutational burden (TMB) may predict immunotherapy response in solid tumors. Response to immune checkpoint inhibitor (ICI) treatment in the rare gliomas with biallelic mismatch repair deficiencies have been attributed to their hypermutation phenotype (HMP). This has not been tested in other gliomas. We developed a phase II clinical trial using nivolumab in recurrent IDH-mutant gliomas evaluating response in tumors with HMP (approximately 10% of cases) and in tumors with non-HMP (NHMP). Here we report the results of the interim analysis of the NHMP cohort. Methods: Adults with recurrent IDH-mutant glioma, KPS ≥ 60, normal organ function, with known somatic TMB (analyzed at NIH) were enrolled to a phase II trial. Nivolumab is given at 480mg IV every 28-day cycle with a maximum of 16 cycles. The primary endpoint is PFS rate at 6 months (PFS6) in both HMP and NHMP cohorts. Responses to treatment are evaluated by MRI every 2 cycles using iRANO criteria. A Simon’s two-stage design was used for conducting the HMP/NHMP cohort independently. For NHMP cohort, the null and alternative hypotheses for PFS6 are 0.3 and 0.5, respectively. Fifteen patients were planned to accrue in stage I. If ≥10 have disease progression at 6 months, the cohort will be terminated, otherwise continue to stage II and accrue additional 31 patients, resulting a total cohort size of 46. The design controls the type I error at 0.05 and yields a power of 0.8. Tumor samples and peripheral blood were collected for correlative studies. Patient-reported outcomes (PRO) were evaluated by longitudinal symptom burden analysis using Brain Tumor Module of the MD Anderson Symptom Inventory. Results: As of May 2022, 17 patients were enrolled to NHMP cohort and 15 were treated (TMB˂5 mut/Mb). Among 15 evaluable patients, 10 were male, median age 39.5 and KPS 90. Histological diagnosis included 12 astrocytoma (grade 3, n = 4; grade 4, n = 8) and oligodendroglioma (grade 2, n = 1; grade 3, n = 2). Median number of prior recurrences is 3. At the time of interim analysis, four patients were receiving ongoing treatment, but all have received more than 6 cycles, with 100% PRO completion. Eleven patients were off study treatment, 2 completed all 16 cycles, 9 had disease progression. Six out of 15 (40%) patients were progression free at 6 months. Per design, the NHMP cohort proceeded to stage II. One treatment related grade 3 immune-related colitis was reported. Conclusions: Nivolumab is well tolerated and has demonstrated efficacy in a cohort of patients with recurrent IDH-mutant gliomas with low TMB. Accrual to this NHMP cohort continues along with continued enrollment to the HMP cohort. Clinical benefit measured by objective response, PFS, OS and longitudinal PRO measure along with longitudinal immune monitoring will help address whether TMB correlates with tumor, immunologic and clinical response, and benefit of ICI therapy in IDH-mutant gliomas. Clinical trial information: NCT03718767 .

PTEN potentiation of oncolytic HSV therapy for glioblastoma

PTEN potentiation of oncolytic HSV therapy for glioblastoma

STAT1 negatively regulates human glioma U251 cell proliferation Huang et al: Role of STAT1 in glioma

Background Glioma is one of the most malignant tumors, which leads to high mortality in cancer patients. At present, there is no effective therapy for glioma. Therefore, it is urgent and necessary to find new molecular targets for anti-glioma therapy. Objective The present study aimed to investigate the role of signal transducer and activator of transcription 1 (STAT1) in the development and progression of human glioma and related mechanisms. Methods According to the instructions of Lipofectamine TM2000 transfection reagent, we transiently transfected the plasmid pcDNA3.1-STAT1 into glioma U251 cells. Then STAT1 expression in glioma U251 and LN382 cells was detected by Western blot. MTT was performed to assay the proliferative activity of U251 cells after STAT1 transduction, flow cytometry was used to detect cell cycle and apoptosis indicators, cell migration indicator was determined by Wound healing, and Western blot was used for detecting the expression level and change trend of p53, p21, bcl-2, Caspase-8, Cyclin A and Cyclin E in transfected cells. Results Overexpressed STAT1 significantly inhibited U251 cell proliferation and promoted U251 cell apoptosis. Meanwhile, high expression of STAT1 can increase the expression of p53, p21, and Caspase-8 while inhibiting the expression of bcl-2, Cyclin A, and Cyclin E. Conclusion Highly expressed STAT1 inhibits the proliferative activity of human glioma U251 cells and can promote tumor cell apoptosis and block cell cycle progression while regulating the expression of various signal transduction molecules. Thus, STAT1 has a critical function in the development and progression of glioma and is a novel target for glioma therapy.

Challenges and advances for glioma therapy based on inorganic nanoparticles

Glioma is one of the most serious central nervous system diseases, with high mortality and poor prognosis. Despite the continuous development of existing treatment methods, the median survival time of glioma patients is still only 15 months. The main treatment difficulties are the invasive growth of glioma and the obstruction of the blood-brain barrier (BBB) to drugs. With rapid advancements in nanotechnology, inorganic nanoparticles (INPs) have shown favourable application prospects in the diagnosis and treatment of glioma. Due to their extraordinary intrinsic features, INPs can be easily fabricated, while doping with other elements and surface modification by biological ligands can be used to enhance BBB penetration, targeted delivery and biocompatibility. Guided glioma theranostics with INPs can improve and enhance the efficacy of traditional methods such as chemotherapy, radiotherapy and gene therapy. New strategies, such as immunotherapy, photothermal and photodynamic therapy, magnetic hyperthermia therapy, and multifunctional inorganic nanoplatforms, have also been facilitated by INPs. This review emphasizes the current state of research and clinical applications of INPs, including glioma targeting and BBB penetration enhancement methods, in vivo and in vitro biocompatibility, and diagnostic and treatment strategies. As such, it provides insights for the development of novel glioma treatment strategies.