Journal articles on the topic 'GBM approach'
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Skarkova, Veronika, Marketa Krupova, Barbora Vitovcova, Adam Skarka, Petra Kasparova, Petr Krupa, Vera Kralova, and Emil Rudolf. "The Evaluation of Glioblastoma Cell Dissociation and Its Influence on Its Behavior." International Journal of Molecular Sciences 20, no. 18 (September 18, 2019): 4630. http://dx.doi.org/10.3390/ijms20184630.
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Purpose: Primary cell lines are a valuable tool for evaluation of tumor behavior or sensitivity to anticancer treatment and appropriate dissociation of cells could preserve genomic profile of the original tissue. The main aim of our study was to compare the influence of two methods of glioblastoma multiforme (GBM) cell derivation (mechanic—MD; enzymatic—ED) on basic biological properties of thus derived cells and correlate them to the ones obtained from stabilized GBM cell line A-172. Methods: Cell proliferation and migration (xCELLigence Real-Time Cell Analysis), expression of microRNAs and protein markers (RT-PCR and Western blotting), morphology (phase contrast and fluorescent microscopy), and accumulation of temozolomide (TMZ) and its metabolite 5-aminoimidazole-4-carboxamide (AIC) inside the cells (LC-MS analysis) were carried out in five different samples of GBM (GBM1, GBM2, GBM32, GBM33, GBM34), with each of them processed by MD and ED types of isolations. The same analyses were done in the A-172 cell line too. Results: Primary GBM cells obtained by ED or MD approaches significantly differ in biological behavior and properties of these cells. Unlike in primary MD GBM cells, higher proliferation, as well as migration, was observed in primary ED GBM cells, which were also associated with the acquired mesenchymal phenotype and higher sensitivity to TMZ. Finally, the same analyses of stabilized GBM cell line A-172 revealed several important differences in measured parameters. Conclusions: GBM cells obtained by MD and ED dissociation show considerable heterogeneity, but based on our results, MD approach should be the preferred method of primary GBM cell isolation
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Verma, Amit, Swetha Gunasekar, Vineeta Goel, Randeep Singh, Ramandeep Singh Arora, Nitesh Rohatgi, A. K. Anand, and Meenu Walia. "A molecular approach to Glioblastoma Multiforme." International Journal of Molecular and Immuno Oncology 1, no. 1 (November 25, 2016): 35. http://dx.doi.org/10.18203/issn.2456-3994.intjmolimmunooncol20164387.
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<p>Glioma is a tumor of the central nervous system that occurs in the glial cells, Which it surrounds and protects the nerve cells. Glioblastoma Multiforme (GBM) is the most common and malignant sub-type of gliomas that arises from star-shaped cells called “astrocytes”, which constitute the supportive tissue of the brain. GBM are known to be heterogeneous in outcome with majority having a poor prognosis, thus there is an urgent need for novel therapeutic approaches. The detailed understanding of GBM is established by the combination of histopathology and genomic information of the tumor that aids in the best choice of Personalized Medicine. In this article, seven GBM patients are discussed who underwent tissue diagnosis as well as tumor molecular profiling; the significance of the genes and associated mutations/variations picked up in each individual.</p>
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Friedmann-Morvinski, Dinorah, Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw, Yasushi Soda, and Inder M. Verma. "Targeting NF-κB in glioblastoma: A therapeutic approach." Science Advances 2, no. 1 (January 2016): e1501292. http://dx.doi.org/10.1126/sciadv.1501292.
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Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)–binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM.
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Pirmoradi, Leila, Nayer Seyfizadeh, Saeid Ghavami, Amir A. Zeki, and Shahla Shojaei. "Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy." Journal of Investigative Medicine 67, no. 4 (February 14, 2019): 715–19. http://dx.doi.org/10.1136/jim-2018-000962.
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Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.
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Tran, David, Son Le, Bo Ma, Darin Falk, and Serge Zolotukhin. "EXTH-51. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING ARTIFICIAL INTELLIGENCE (AI)-DIRECTED IDENTIFICATION OF THE GBM STATE." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi174—vi175. http://dx.doi.org/10.1093/neuonc/noab196.690.
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Abstract BACKGROUND Profound heterogeneity has severely hampered therapeutic advancements in GBM. Remarkably, however, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common state. The GBM state embodies network restructuring forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSCs). Successful targeting of the GBM state promises to circumvent the heterogeneity. METHODS To decipher the GBM state, we applied NETZEN, an AI suite integrating a deep neural network with gene network-based ranking, to first generate the reference GBM gene network from TCGA’s entire GBM RNAseq collection, and then identify the altered master regulatory gene subnetwork in GBM using a dataset containing >30 diverse patient-derived GSC lines and their paired differentiated cells, 6 astrocyte and 3 neuronal precursor cell lines. To develop a gene therapy against the GBM state, we screened a rAAV capsid library through GBM patient-derived xenografts (PDX) to identify variants with specific tropism for GBM cells that can deliver targeting constructs intratumorally. RESULTS We discovered a putative GBM state anchored by developmentally restricted master regulators. To validate its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed improved tumor control and survival compared to controls (p< 0.05 in all lines). More notably, when the core GBM state was forcibly reconstructed in astrocytes, transformation into GSC-like cells occurred, as measured by single-cell analysis, neurosphere formation, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel rAAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based rAAV platform to target key master regulators of the validated GBM state. CONCLUSIONS The GBM state is established by a developmental master regulator subnetwork permitting the creation of a first-of-its-kind, heterogeneity-agnostic GBM therapy. This AI-directed R&D program can be expanded to target other tumors.
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Lee, Ho-Sung, In-Hee Lee, Sang-In Park, Minho Jung, Seung Gu Yang, Tae-Wook Kwon, and Dae-Yeon Lee. "Unveiling the Mechanism of the Traditional Korean Medicinal Formula FDY003 on Glioblastoma Through a Computational Network Pharmacology Approach." Natural Product Communications 17, no. 9 (September 2022): 1934578X2211263. http://dx.doi.org/10.1177/1934578x221126311.
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Glioblastoma (GBM) is the most common type of primary malignant tumor that develops in the brain, with 0.21 million new cases per year globally and a median survival period of less than 2 years after diagnosis. Traditional Korean medicines have been increasingly suggested as effective and safe therapeutic strategies for GBM. However, their pharmacological effects and mechanistic characteristics remain to be studied. In this study, we employed a computational network pharmacological approach to determine the effects and mechanisms of the traditional Korean medicinal formula FDY003 on GBM. We found that FDY003 treatment decreased the viability of human GBM cells and increased their response to chemotherapeutics. We identified 10 potential active pharmacological compounds of FDY003 and 67 potential GBM-related target genes and proteins. The GBM-related targets of FDY003 were signaling components of various crucial GBM-associated pathways, such as PI3K-Akt, focal adhesion, MAPK, HIF-1, FoxO, Ras, and TNF. These pathways are functional regulators for the determination of cell growth and proliferation, survival and death, and cell division cycle of GBM cells. Together, the overall analyses contribute to the pharmacological basis for the anti-GBM roles of FDY003 and its systematic mechanisms.
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Zupancic, Klemen, Andrej Blejec, Ana Herman, Matija Veber, Urska Verbovsek, Marjan Korsic, Miomir Knezevic, et al. "Identification of plasma biomarker candidates in glioblastoma using an antibody-array-based proteomic approach." Radiology and Oncology 48, no. 3 (September 1, 2014): 257–66. http://dx.doi.org/10.2478/raon-2014-0014.
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Abstract Background. Glioblastoma multiforme (GBM) is a brain tumour with a very high patient mortality rate, with a median survival of 47 weeks. This might be improved by the identification of novel diagnostic, prognostic and predictive therapy-response biomarkers, preferentially through the monitoring of the patient blood. The aim of this study was to define the impact of GBM in terms of alterations of the plasma protein levels in these patients. Materials and methods. We used a commercially available antibody array that includes 656 antibodies to analyse blood plasma samples from 17 healthy volunteers in comparison with 17 blood plasma samples from patients with GBM. Results. We identified 11 plasma proteins that are statistically most strongly associated with the presence of GBM. These proteins belong to three functional signalling pathways: T-cell signalling and immune responses; cell adhesion and migration; and cell-cycle control and apoptosis. Thus, we can consider this identified set of proteins as potential diagnostic biomarker candidates for GBM. In addition, a set of 16 plasma proteins were significantly associated with the overall survival of these patients with GBM. Guanine nucleotide binding protein alpha (GNAO1) was associated with both GBM presence and survival of patients with GBM. Conclusions. Antibody array analysis represents a useful tool for the screening of plasma samples for potential cancer biomarker candidates in small-scale exploratory experiments; however, clinical validation of these candidates requires their further evaluation in a larger study on an independent cohort of patients.
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Benouaich Amiel, A., V. Khasminsky, O. Gal, S. Fichman, T. Weiss, T. Siegal, and S. Yust-Katz. "P14.72 Multicentric glioblastoma - A retrospective study of imaging characteristics, treatment approach, pattern of relapse and survival." Neuro-Oncology 21, Supplement_3 (August 2019): iii84. http://dx.doi.org/10.1093/neuonc/noz126.307.
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Abstract BACKGROUND Multicentric glioblastoma (m-GBM), defined as well separated tumoral foci, is a rare GBM variant comprising 6–13% of all GBM cases. Published data regarding m-GBM is scarce and is largely reporting on multicentric enhancing foci. We performed a retrospective study to determine the incidence, imaging characteristics, treatment approach, pattern of relapse and prognosis of m-GBM. MATERIAL AND METHODS The neuropathological database of our institution was surveyed for histological diagnosis of adult GBM diagnosed between 01/01/2015 and 31/05/2018. All pre-operative MRI were reviewed to identify patients with m-GBM. We included in the definition of m-GBM well separated enhancing as well as non-enhancing tumor foci. The medical records and follow-up MRI studies were reviewed in order to retrieve the data. RESULTS Of the 170 patients with newly diagnosed GBM 14 (8%) presented with m-GBM. All of them had at least one enhancing lesion and 11 (78.5%) patients had additional well separated non-enhancing tumor foci. The total number of lesions was 37 (19 enhancing and 18 non-enhancing) with a median number of lesions per patient of 2 (range 2 to 4). Median age at diagnosis was 66 (range: 49–79) years. Nine of the patients (64%) underwent surgical resection of the enhancing component whereas 5 patients had only a biopsy. Median follow up was 14.3 (range: 2–30) months. All but one patients were treated by standard concurrent radiotherapy with temozolomide. Median progression free survival is 6.2 (range: 0–13.3) months. Five of the 18 non-enhancing tumor foci eventually displayed contrast enhancement during the course of the disease. At last follow up, 12 patients died, with an overall survival of 12.3 months. Information regarding radiation fields, pattern of disease progression and molecular profile will be presented at the meeting. CONCLUSION m-GBM presents therapeutic dilemas regarding the optimal surgical approach and radiation field planning. Better understanding of the disease course and pattern of progression may help to optimize the therapeutic approach implying particularly to non-enhancing tumor foci.
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D’Amico, Agata Grazia, Grazia Maugeri, Luca Vanella, Valeria Pittalà, Dora Reglodi, and Velia D’Agata. "Multimodal Role of PACAP in Glioblastoma." Brain Sciences 11, no. 8 (July 28, 2021): 994. http://dx.doi.org/10.3390/brainsci11080994.
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Glioblastoma multiforme (GBM) is the deadliest form of brain tumors. To date, the GBM therapeutical approach consists of surgery, radiation-therapy and chemotherapy combined with molecules improving cancer responsiveness to treatments. In this review, we will present a brief overview of the GBM classification and pathogenesis, as well as the therapeutic approach currently used. Then, we will focus on the modulatory role exerted by pituitary adenylate cyclase-activating peptide, known as PACAP, on GBM malignancy. Specifically, we will describe PACAP ability to interfere with GBM cell proliferation, as well as the tumoral microenvironment. Considering its anti-oncogenic role in GBM, synthesis of PACAP agonist molecules may open new perspectives for combined therapy to existing gold standard treatment.
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Oh, Michael, Mohammad Hasanain, Simona Migliozzi, Luciano Garofano, Fulvio D'Angelo, Anna Luisa Di Stefano, Julie Lerond, et al. "EXTH-21. DEVELOPMENT OF THERAPEUTIC STRATEGIES BY PATHWAY-BASED MULTI-OMICS APPROACH AND MASTER KINASE ANALYSIS IN GLIOBLASTOMA MULTIFORME." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii214. http://dx.doi.org/10.1093/neuonc/noac209.820.
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Abstract Current transcriptomic classification of Glioblastoma Multiforme (GBM) has been ineffective to predict survival and therapeutic vulnerabilities. Recently, we proposed a four-group functional classification of GBM that included proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic subtypes with prognostic and therapeutic implications as the mitochondrial subtype carries the best survival and exhibits distinct sensitivity to mitochondrial OXPHOS inhibitors. To uncover novel therapeutic targets for each functional GBM subtype, we focused on protein kinases for their attractive features as both drivers and drug targets, with current availability of 62 FDA-approved inhibitors available for cancer precision therapeutics. We designed an unbiased integrative, machine learning-based proteomics/phosphoproteomics network for the identification of Master Kinases (MKs) responsible for effecting key phenotypic hallmarks of each of the four GBM subtypes. Here we report the identification and validation of protein kinase C delta (PRKCd) and DNA-PKcs as MKs that sustain the glycolytic/plurimetabolic and proliferative/progenitor GBM subtypes, respectively. Genetic and pharmacologic inactivation of PKCd in GBM patient-derived organoids of the glycolytic/plurimetabolic subtype blocked glucose uptake and lipid accumulation, resulting in marked anti-tumor effects. We also validated the role of PKCd in oncometabolic processes at the intersection between insulin, IGF, and lipid metabolism. DNA-PKcs was qualified as MK for the proliferative/progenitor GBM subtype, which is characterized by high basal level of replication stress. Biochemical experiments showed activation of DNA-PK in GBM patient-derived organoids of the proliferative/progenitor subgroup. Targeting DNA-PK in proliferative/progenitor GBM organoids with the clinically tested DNA-PKcs inhibitor nedisertib in association with gamma irradiation, the essential component of the standard of care for patients with GBM, led to an unsustainable level of DNA damage and massive GBM cell death selectively in this GBM subtype. As DNA-PKcs inhibitors have been introduced into clinical trials, our findings suggest that pre-selection of patient with PPR tumors is likely to enhance therapeutic success.
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Desai, Vilas, and Alok Bhushan. "Natural Bioactive Compounds: Alternative Approach to the Treatment of Glioblastoma Multiforme." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/9363040.
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Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach for the effective treatment of cancer. In this paper, we review the role of several natural compounds individually and in combination with chemotherapeutic agents in the treatment of GBM. We also assess the potential of drug delivery approaches such as the Gliadel wafers and role of nanomaterial based drug delivery systems for the effective treatment of GBM.
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Sloan, Anthony, Harry Hoffman, Peggy Harris, Christine Lee-Poturalski, Theresa Elder, Amber Kerstetter-Fogle, Gino Cioffi, et al. "STEM-17. THE GLIOMA STEM CELL PLATELET INTERACTION DRIVES GBM ONCOGENESIS IDENTIFYING A NOVEL THERAPEUTIC APPROACH." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi24. http://dx.doi.org/10.1093/neuonc/noab196.091.
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Abstract The effect of platelets on oncogenesis has been studied extensively in cancer metastasis, but not in glioblastoma (GBM), where metastasis is rare. Here we identify the unique crosstalk between glioma stem cells (GSCs) and platelets within GBM solid tumors that enhance disease progression. Targeting GSCs is considered a promising therapeutic approach; however, no clear method has been identified. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Immunofluorescence, qPCR, and western blot were used to evaluate the presence of GSCs and platelets and their colocalization in GBM patient tissue at University Hospitals-Seidman Cancer Center. Functional assays followed by RNA sequencing were conducted to determine the functional effect of healthy and GBM platelets on growth of patient derived, autologous GSCs. Our clinical studies suggest elevated platelet counts positively correlate with GSC proliferation and negatively correlate with overall survival in patients with GBM. Patients with high platelet counts ( >350k/µl) had a median survival time of 9 months compared to 16 months median survival for patients with normal platelet count (150-350/µl) (p<0.05). We demonstrate platelet and GSC co-localization in GBM solid tissue and platelet exposure to patient derived GSCs cell lines results in a ≥ 3-fold increase in GSC proliferation compared to GSCs not exposed to platelets (p<0.0005). Similarly we found that platelets increased the self-renewing capacity by enhancing the average sphere size (p < 0.005), and increasing the GSC “Stem-like” transcriptional pattern (P< 0.05). Conversely, pharmacologic inhibition of platelet activation reversed the effect of platelets on GSC proliferation (p ranging from 0.05-0.005). These studies suggests the platelet-GSC interactions appear to stimulate GBM oncogenesis, identifying a potential therapeutic target for the treatment of GBM.
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Wang, Jiao, and Sandro Matosevic. "150 Targeted delivery of a PD-L1-blocking scFv by CAR-NK cells shows potential as a new approach to immunotherapy for glioblastoma." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A158. http://dx.doi.org/10.1136/jitc-2021-sitc2021.150.
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BackgroundDespite advances in treatment, glioblastoma (GBM) remains an incurable primary brain tumor with a median survival of only 15 months, highlighting the need for new therapeutic approaches. Natural killer (NK) cells, innate cytotoxic effectors, are showing potential for cancer immunotherapy including GBM. Even though GBM tumors are infiltrated by NK cells.1 However, their antitumor activities are impaired by the immunosuppressive tumor microenvironment (TME) via various mechanisms, including adenosine-mediated downregulation of NKG2D.2 Therefore, it is critical to understand more about how the TME in GBM modulates the NK cell-mediated immunity so that we can develop novel NK cell-based therapies specifically for GBM.MethodsWe isolated human peripheral blood NK cells from healthy volunteer donors. U87MG and GBM43 were used as GBM targets. We co-cultured NK cells with GBM cells and measured the PD-L1 expression on the NK cells. We built a transwell co-culture system to evaluate the crosstalk between NK and GBM cells on the PD-L1 expression on GBM target cells. We then generated gene-modified NK cells expressing an NKG2D.CAR which secretes anti-PD-L1 scFv locally in the TME. These NK cells are being evaluated for their efficacy against GBM both in vitro and in vivo.ResultsWe have found that GBM target cells can upregulate PD-L1 expression on NK cells (figure 1A). And induced PD-L1+ NK cells present better in vitro anti-GBM activity, including higher killing, degranulation and IFN-γ release (figure 1B). We have revealed that the expression of PD-L1 on GBM cells gets further boosted after crosstalk with NK cells, which is dependent on the induced IFN-γ release (figure 1C). Accordingly, we have designed and synthesized a multifunctional CAR construct that enables NK cells to express a secretable PD-L1-blocking scFv and a CAR redirected against ligands for NKG2D (figure 1D).Abstract 150 Figure 1(A) PD-L1 expression on human primary NK cells after co-incubation with different types of cancer target cells, including U87MG (human glioblastoma cell line) and GBM43 (a human patient-derived glioblastoma cell) cells at a E/T ratio of 10 for 24 h, respectively; (B) In vitro anti-GBM activities of PD-L1- NK cells vs PD-L1+ NK cells, including killing, degranulation (CD107a), and IFN-γ secretion; (C) Setup of transwell system for evaluation of PD-L1 expression on GBM target cells upon co-culture with NK cells; (E) Multifunctional genetically-engineered NK cells for GBM immunotherapy. Data are presented as the mean ± SEMConclusionsAfter direct contact with GBM cells, the increased population of PD-L1+ NK cells with superior cytolytic functions have been found for the first time. Also, NK cells co-cultured with GBM cells can further trigger PD-L1 upregulation on GBM cells. Stimulated by these results, we have been generating NK cells that can, at once, secrete the PD-L1-blocking scFv to target PD-L1 both expressed on NK and GBM cells, and express the NKG2D.CAR to specifically target its ligands on GBM cells. We are currently testing the in vitro and in vivo therapeutic efficacy of these engineered NK cells, which we believe could be used as a promsing immunotherapy for GBM.ReferencesWang J, Matosevic S. NT5E/CD73 as correlative factor of patient survival and natural killer cell infiltration in glioblastoma. J Clin Med 2019;8(10):1526.Wang J, Lupo KB, Chambers AM, Matosevic S. Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J Immunother Cancer 2018;6(1):136.
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Le, Son, Bo Ma, Sergei Zolotukhin, Darin Falk, and David Tran. "STEM-18. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING AI-DIRECTED IDENTIFICATION OF A MASTER REGULATORY GENE NETWORK." Neuro-Oncology 22, Supplement_2 (November 2020): ii200. http://dx.doi.org/10.1093/neuonc/noaa215.835.
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Abstract BACKGROUND Profound heterogeneity has severely hampered therapeutic advancements in glioblastoma (GBM). Remarkably, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common regulatory state. The GBM state embodies restructuring of the master regulatory gene network (MRGN) forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSC). Successful targeting and altering of the MRGN promise to circumvent the heterogeneity. METHODS To decipher the common MRGN in GSC, we applied a robust AI suite, NETZEN, that integrates deep neural networks with gene network-based ranking to the reference GBM network generated using TCGA’s entire GBM RNAseq dataset and a dataset containing > 30 diverse GSC and paired GBM differentiated cell lines, 6 normal astrocyte and 3 normal neuronal precursor cell lines. To develop a gene therapy against the MRGN, we performed a screen of a rAAV capsid library using GBM patient-derived orthotopic xenografts (PDX) to identify capsid variants with specific tropism for GBM cells to deliver shRNA-based cassettes. RESULTS We discovered a putative MRGN in GSC, anchored by developmentally restricted master regulators (MR). To confirm its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed attenuated tumor growth and mortality compared to controls (p < 0.05 in all lines). More notably, when normal astrocytes were forced to reconstruct the MRGN, transformation into GSC-like cells occurred, as measured by single-cell analysis, sphere formation in vitro, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel AAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based AAV platform to target key MR in the validated MRGN. CONCLUSIONS The GBM state is established by a developmental subnetwork permitting a first-of-its-kind, heterogeneity-agnostic AAV-based treatment approach. This AI-directed R&D program can be expanded to target other cancers.
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Benouaich-amiel, Alexandra, Vadim Khasminsky, Omer Gal, Tamara Weiss, Suzana Fichman, Tali Siegal, and Shlomit Yust-Katz. "NIMG-04. MRI CHARACTERISTICS, TREATMENT APPROACH, PATTERN OF RELAPSE AND SURVIVAL FOR MULTICENTRIC GLIOBLASTOMA. A RETROSPECTIVE MONOCENTRIC STUDY." Neuro-Oncology 21, Supplement_6 (November 2019): vi162. http://dx.doi.org/10.1093/neuonc/noz175.676.
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Abstract INTRODUCTION Multicentric glioblastoma (m-GBM) is a rare GBM variant (6–13% of all GBM cases). Published data is scarce and focus largely on enhancing foci. We performed a retrospective study to determine the incidence, imaging characteristics, treatment, pattern of relapse and prognosis of m-GBM. METHODS The neuropathological database of our institution was surveyed for histological diagnosis of adult GBM diagnosed between 01/01/2015 and 31/05/2018. All pre-operative MRI were reviewed to identify patients with m-GBM (defined as well separated enhancing and non-enhancing tumor foci). Medical records and follow-up MRI studies were reviewed to retrieve the data. RESULTS Of the 167 patients with newly diagnosed GBM, 14 (8%) presented with m-GBM. All of them had at least one enhancing lesion. The total number of lesions was 37 (19 enhancing and 18 non-enhancing) with a median number of lesions per patient of 2 (range 2 to 4). Median age at diagnosis was 66 (range: 49–79) years. MGMT status was known for 10 patients (5 methylated and 5 un-methylated). Nine patients underwent resection of the enhancing component whereas 5 patients had a biopsy. Median follow up was 14.3 (range: 2–30) months. All but one patient were treated by concurrent radiotherapy with temozolomide. All enhancing lesions were included in radiation field, whereas 4 of the 18 Flair lesions were not. Median progression free survival was 6.2 (range: 0–13.3) months. Six of the 18 non-enhancing tumor foci eventually displayed contrast enhancement during the follow-up. At last follow up, 12 patients died, with an overall survival of 12.3 months. Information regarding radiation fields, pattern of progression and molecular profile will be presented at the meeting. CONCLUSION m-GBM presents therapeutic dilemmas regarding the optimal therapeutical approach. Better understanding of the disease course and pattern of progression may help to optimize the therapeutic approach implying particularly to non-enhancing tumor foci.
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Lajoie, Ginette. "Approach to the Diagnosis of Thin Basement Membrane Nephropathy in Females With the Use of Antibodies to Type IV Collagen." Archives of Pathology & Laboratory Medicine 125, no. 5 (May 1, 2001): 631–36. http://dx.doi.org/10.5858/2001-125-0631-attdot.
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Abstract Context.—Thin basement membrane nephropathy is recognized by a diffusely thin glomerular basement membrane (GBM) ultrastructurally. In contrast to Alport syndrome (AS), there is no GBM thickening, lamellation, or granular inclusions. Morphologically, there is overlap between thin basement membrane nephropathy and AS in female patients in whom there might be only thin GBM and no pathognomonic findings of AS. Objective.—To determine if the use of antibodies to collagen IV is helpful in making the distinction between thin basement membrane nephropathy and AS in female patients with primarily thin GBMs. Design.—We examined renal biopsies from 9 adult female patients with thin GBMs for the presence of α1, α3, α4, and α5 chains of type IV collagen by immunofluorescence. Results.—In 2 patients with segmental GBM staining, no suggestion for AS was found on physical examination or in their family history. In the remaining 7 patients with normal GBM staining, 4 had family members with end-stage renal disease of unknown etiology, raising the suspicion of X-linked or autosomal-recessive AS. Three patients were presumed to have thin basement membrane nephropathy. Conclusion.—Segmental GBM staining for α3, α4, and α5 chains of type IV collagen raises the suspicion of AS in the presence of adequate controls and other supporting evidence. Normal GBM staining for α3, α4, and α5 chains of type IV collagen, however, does not exclude AS.
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Doan, Phuong, Phung Nguyen, Akshaya Murugesan, Nuno R. Candeias, Olli Yli-Harja, and Meenakshisundaram Kandhavelu. "Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity." Cells 10, no. 8 (August 3, 2021): 1975. http://dx.doi.org/10.3390/cells10081975.
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Drug resistance and tumor heterogeneity limits the therapeutic efficacy in treating glioblastoma, an aggressive infiltrative type of brain tumor. GBM cells develops resistance against chemotherapeutic agent, temozolomide (TMZ), which leads to the failure in treatment strategies. This enduring challenge of GBM drug resistance could be rational by combinatorial targeted therapy. Here, we evaluated the combinatorial effect of phenolic compound (2-(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), GPR17 agonist 2-({5-[3-(Morpholine-4-sulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)-N-[4-(propan-2-yl)phenyl]acetamide (T0510.3657 or T0) with the frontline drug, TMZ, on the inhibition of GBM cells. Mesenchymal cell lines derived from patients’ tumors, MMK1 and JK2 were treated with the combination of THTMP + T0, THTMP + TMZ and T0 + TMZ. Cellular migration, invasion and clonogenicity assays were performed to check the migratory behavior and the ability to form colony of GBM cells. Mitochondrial membrane permeability (MMP) assay and intracellular calcium, [Ca2+]i, assay was done to comprehend the mechanism of apoptosis. Role of apoptosis-related signaling molecules was analyzed in the induction of programmed cell death. In vivo validation in the xenograft models further validates the preclinical efficacy of the combinatorial drug. GBM cells exert better synergistic effect when exposed to the cytotoxic concentration of THTMP + T0, than other combinations. It also inhibited tumor cell proliferation, migration, invasion, colony-forming ability and cell cycle progression in S phase, better than the other combinations. Moreover, the combination of THTMP + T0 profoundly increased the [Ca2+]i, reactive oxygen species in a time-dependent manner, thus affecting MMP and leading to apoptosis. The activation of intrinsic apoptotic pathway was regulated by the expression of Bcl-2, cleaved caspases-3, cytochrome c, HSP27, cIAP-1, cIAP-2, p53, and XIAP. The combinatorial drug showed promising anti-tumor efficacy in GBM xenograft model by reducing the tumor volume, suggesting it as an alternative drug to TMZ. Our findings indicate the coordinated administration of THTMP + T0 as an efficient therapy for inhibiting GBM cell proliferation.
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Skirboll, Stephen, Natasha Lucki, Genaro Villa, Naja Vergani, Michael Bollong, Brittney Beyer, Jae Wook Lee, et al. "STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM." Neuro-Oncology 22, Supplement_2 (November 2020): ii200. http://dx.doi.org/10.1093/neuonc/noaa215.837.
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Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.
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Sherman, Wendy, Katie Martin, Larissa Rossell, Kelly Nguyen, Pamela Grady, Cynthia Zimmermann, David Chesla, and Jeffrey Mackeigan. "EPCO-24. COMPUTATIONAL APPROACH TO IDENTIFYING NEUROINFLAMMATION IN GLIOBLASTOMA MULTIFORME (GBM)." Neuro-Oncology 22, Supplement_2 (November 2020): ii74. http://dx.doi.org/10.1093/neuonc/noaa215.303.
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Abstract INTRODUCTION Glioblastoma multiforme (GBM) is an aggressive brain cancer with dismal prognosis, despite aggressive surgery, radiation and chemotherapy. Therapies directed to the immune system are an exciting prospect in oncology and require an understanding of the interaction between tumors and immune cells. Our objective was to use computational tools to estimate immune infiltration in GBM and determine whether specific immune cell types are associated with clinical outcomes. METHODS RNA sequencing and targeted DNA sequencing (to 981 oncology genes) was performed from 37 surgically-resected GBM tumors. Tumor mutations were identified, and gene-level transcript counts were used to estimate tumor-associated cell types using bioinformatics tools. Clinical variables, including survival from surgery and diagnosis, were collected and tested for associations with molecular data. RESULTS We detected leukocyte fractions (i.e., immune infiltration) ranging from 2% to 50% in GBMs, with an average of 10.2%. Specifically, we found a statistically significant association between high Th2 cell estimates and reduced overall survival (from both surgery and diagnosis). Nine patients with high Th2 tumors had a median OS from surgery of 187 days, compared with a median of 454 days for 28 patients with low Th2 tumors (log-rank Matel-Cox test; p = 0.0023, HR = 3.1). We also found an association between NF1 mutant tumors, which were enriched for a KRAS signaling signature, and high immune infiltration (p < 0.05). CONCLUSION Our computationally-driven approach predicted significant immune infiltration in GBM and a potential association between poor prognosis and Th2 cells. The specific class of CD4+ helper T-cells is generally associated with poor anti-tumor immunity and a Th2-bias has been reported in gliomas. Our data adds to the collective understanding of the molecular landscape of GBM, as well as the complex immune environment, which will have important implications in tumor treatment and prognosis.
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Shojaei, Shahla, Javad Alizadeh, James Thliveris, Navid Koleini, Elissavet Kardami, Grant M. Hatch, Fred Xu, Sabine Hombach-Klonisch, Thomas Klonisch, and Saeid Ghavami. "Statins: a new approach to combat temozolomide chemoresistance in glioblastoma." Journal of Investigative Medicine 66, no. 8 (October 27, 2018): 1083–87. http://dx.doi.org/10.1136/jim-2018-000874.
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Patients with glioblastoma multiforme (GBM) have an average life expectancy of approximately 15 months. Recently, statins have emerged as a potential adjuvant cancer therapy due to their ability to inhibit cell proliferation and induce apoptosis in many types of cancer. The exact mechanisms that mediate the inhibitory actions of statins in cancer cells are largely unknown. The purpose of this proceeding paper is to discuss some of the known anticancer effects of statins, while focusing on GBM therapy that includes adjunct therapy of statins with chemotherapeutic agents.
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Iorio, Anna, Martina Da Ros, Claudio Pisano, Maurizio de Martino, Lorenzo Genitori, and Iacopo Sardi. "Combined Treatment with Doxorubicin and Rapamycin Is Effective against In Vitro and In Vivo Models of Human Glioblastoma." Journal of Clinical Medicine 8, no. 3 (March 9, 2019): 331. http://dx.doi.org/10.3390/jcm8030331.
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Despite numerous clinical trials, glioblastoma (GBM) remains a tumor that is difficult to treat. The aim of this study was to investigate the potential of a new pharmacological approach, combining doxorubicin (Dox) and rapamycin (Rapa), in in vitro and in vivo GBM models. Cytotoxic and anti-proliferative effects of Rapa plus Dox treatments were analyzed in GBM cell lines. The in vivo effectiveness of these treatments was investigated in an orthotopic xenograft mice model of GBM. In vitro results demonstrated that prolonged exposure to Rapa sensitize GBM cells to Dox treatments. In vivo results demonstrated that Rapa (5 mg/kg) plus Dox (5 mg/kg) determined the major tumor growth inhibition (−97.29% vs. control) but results in greater toxicity. The combination Rapa plus Dox (2.5 mg/kg) showed a tumor inhibition like Rapa plus Dox (5 mg/kg) with a toxicity comparable to Rapa alone. Thus, this study demonstrated the efficacy of this pharmacological approach, providing the rationale for a clinical application of this combinational therapy in “poor-responder” GBM patients.
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Miller, Caroline A., and Dominic Cosgrove. "A Post-Embedding Colloidal Gold Immunocytochemical Approach To The Study Of Matrix Accumulation In Glomerular Basement Membrane." Microscopy and Microanalysis 5, S2 (August 1999): 1336–37. http://dx.doi.org/10.1017/s1431927600020006.
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Alport renal disease pathogenesis is characterized by a progressive irregular thickening, thinning, and splitting of the glomerular basement membrane (GBM), which culminates in a focal and segmental glomerulonephritis and progressive loss of glomerular filtration, leading to uremia and death. A mouse model for this disease was produced using a gene targeting approach (Cosgrove et al., 1996). The resulting model displays renal pathology that is very similar to that observed in humans. As matrix accumulation has long been associated with the thickened regions of the GBM, this model provided a means to study the molecular composition and ultrastructural localization of matrix in these rarefied regions of the GBM in the Alport mouse.We examined three matrix molecules based on preliminary data; type IV collagen α l and α2 chains, laminin-1 and fibronectin. Immunohistochemical analysis showed that while all three of these molecules localize primarily to the mesangial matrix of normal mouse glomeruli, in the Alport glomeruli these molecules seem to be heavily deposited in the GBM.
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J Umlauf, Benjamin, Paul A Clark, Jason M Lajoie, Julia V Georgieva, Samantha Bremner, Brantley R Herrin, Eric V Shusta, and John S Kuo. "SCIDOT-05. DEVELOPING VARIABLE LYMPHOCYTE RECEPTORS THAT TARGET PATHOLOGICALLY EXPOSED NEURAL ECM TO TREAT GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi273. http://dx.doi.org/10.1093/neuonc/noz175.1146.
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Abstract INTRODUCTION The median survival of gliobastoma (GBM) patients remains less than two years despite aggressive treatments. Current targeted GBM therapies demonstrate initial therapeutic benefit; however, patients relapse due to therapeutic resistance and failure to eliminate GBM cells at the invasive margin. Therefore, we propose a two-prong approach: first, target pathologic disruption of the blood brain barrier (BBB) via exposure of neural ECM rather than disease markers to overcome therapy-resistant GBM; and second, designing therapeutic payloads that extracellularly spread throughout the tumor volume. METHODS Variable Lymphocyte Receptors (VLRs, a lamprey-derived antigen recognition system) were identified with high specificity for neural ECM. Candidate VLRs underwent further refinement using ex vivo tissue staining. Utilizing pathologic disruption of BBB as an approach for targeting GBM was confirmed in vivo with intracranial murine glioblastoma models. Finally, an immunogenic peptide was attached via a cleavable linker to the neural ECM binding VLRs for conditional release extracellularly to spread throughout the tumor. RESULTS The lead neural ECM-binding VLR candidate, named P1C10, demonstrates diffuse binding to parenchymal neural ECM, without detectable binding to other tissues. P1C10 demonstrates nanomolar affinity for neural ECM, and preferentially accumulates in intracranial GL261 and U87 murine GBM models. Finally, P1C10-targeted doxorubicin-loaded liposomes significant increased survival of mice with intracranial GBM. In additional studies, treating murine GBM models with a P1C10 VLR linked to an immunogenic peptide reduced GBM proliferation and increased infiltration of cytotoxic T cells. CONCLUSIONS We present proof-of-concept demonstration for targeting intracranial GBM via neural ECM exposed at pathological BBB disrupted sites. Additionally, P1C10 neural ECM-targeting VLR delivers chemotherapy-loaded nanoparticles and immunogenic peptides designed to spread extracellularly throughout the tumor. Thus, this novel strategy links a physiological ECM targeting scheme with extracellular-released therapeutics to treat primary GBM, and has potential for delivering therapies to other CNS diseases with pathological BBB.
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Vasilev, Alex, Roba Sofi, Stuart J. Smith, Ruman Rahman, Anja G. Teschemacher, and Sergey Kasparov. "Feasibility of Photodynamic Therapy for Glioblastoma with the Mitochondria-Targeted Photosensitizer Tetramethylrhodamine Methyl Ester (TMRM)." Biomedicines 9, no. 10 (October 13, 2021): 1453. http://dx.doi.org/10.3390/biomedicines9101453.
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One of the most challenging problems in the treatment of glioblastoma (GBM) is the highly infiltrative nature of the disease. Infiltrating cells that are non-resectable are left behind after debulking surgeries and become a source of regrowth and recurrence. To prevent tumor recurrence and increase patient survival, it is necessary to cleanse the adjacent tissue from GBM infiltrates. This requires an innovative local approach. One such approach is that of photodynamic therapy (PDT) which uses specific light-sensitizing agents called photosensitizers. Here, we show that tetramethylrhodamine methyl ester (TMRM), which has been used to asses mitochondrial potential, can be used as a photosensitizer to target GBM cells. Primary patient-derived GBM cell lines were used, including those specifically isolated from the infiltrative edge. PDT with TMRM using low-intensity green light induced mitochondrial damage, an irreversible drop in mitochondrial membrane potential and led to GBM cell death. Moreover, delayed photoactivation after TMRM loading selectively killed GBM cells but not cultured rat astrocytes. The efficacy of TMRM-PDT in certain GBM cell lines may be potentiated by adenylate cyclase activator NKH477. Together, these findings identify TMRM as a prototypical mitochondrially targeted photosensitizer with beneficial features which may be suitable for preclinical and clinical translation.
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Durairaj, Aarooran, Melanie McReynolds, Congcong Wang, Joy He, Joshua Rabinowitz, Katrin Andreasson, and Paras Minhas. "FSMP-17. GLOBAL METABOLOMIC PROFILING OF GLIOBLASTOMA MULTIFORME REVEALS METABOLIC VULNERABILITIES IN RESPONSE TO RADIATION THERAPY." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i19. http://dx.doi.org/10.1093/noajnl/vdab024.080.
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Abstract Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, originates in astrocytes and oligodendrocytes and yields a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat the poor prognosis of GBM. Recent studies have established that GBM cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived GBM cell lines. Surprisingly, acute high dosage of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), a non-proteinogenic amino acid. Fractionation of radiation therapy resulted in dose-dependent changes in the heme synthesis pathway within these cells. Using an orthotopic xenograft mouse model of GBM, we identify several enzymatic vulnerabilities in vivo and discuss a novel combinatorial therapeutic approach of radiation and targeted pharmacological intervention. Our findings reveal the fundamental biosynthetic changes that GBMs adopt when exposed to ionizing irradiation as well as the benefits of a combinatorial approach.
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Fahimma, Yuyun Yueniwati, Dessika Rahmawati, and Dessika Rahmawati. "Recurrence of glioblastoma multiforme in a childhood: A case report." World Journal of Advanced Research and Reviews 8, no. 3 (December 30, 2020): 407–12. http://dx.doi.org/10.30574/wjarr.2020.8.3.0488.
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GBM is a highly aggressive malignant tumor that rarely happens in children. Pediatric GBM is the primary cause of death in children with brain neoplasms. Treatment of GBM is a difficult and challenging condition, especially in pediatric GBM. Surgical tumor resection combined with chemoradiotherapy suggests as standard therapeutic approaches for GBM. However, the recurrence of GBM is an inevitable event and can occur in more than 90% of patients. We present an unusual case of an 11-years-old girl with recurrence of GBM. She complained of progressive headache and left hemiparesis as an initial manifestation. She was diagnosed with GBM three years before. Near-total surgical resection followed with chemotherapy, and radiotherapy was done after the diagnosis. Head imaging showed a smaller lesion, and her symptoms were improved significantly. Two years after, she was admitted to the hospital with worsening symptoms. Imaging evaluation showed the enlargement of tumor lesions. Recurrence of GBM is a great challenge to manage, and there are no well-defined management protocols. Several studies suggest that treatment options may follow the adult patients' approach, but pediatric GBM has significantly different characteristics than adults.
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Cemeli, Tània, Marta Guasch-Vallés, Marina Ribes-Santolaria, Eva Ibars, Raúl Navaridas, Xavier Dolcet, Neus Pedraza, et al. "Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma." International Journal of Molecular Sciences 23, no. 15 (July 25, 2022): 8199. http://dx.doi.org/10.3390/ijms23158199.
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Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence.
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Rosenblum, Daniel, Anna Gutkin, and Dan Peer. "SCIDOT-40. THERAPEUTIC GENOME EDITING AS A NOVEL TREATMENT FOR GBM." Neuro-Oncology 21, Supplement_6 (November 2019): vi280. http://dx.doi.org/10.1093/neuonc/noz175.1176.
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Abstract Glioblastoma multiforme (GBM), is the most aggressive form of glioma, a brain tumor that arises from glial cells. GBM is considered a complex malignancy with multiple gene mutations, aberrations, and overexpression together with high infiltration rate and resistance to apoptosis. The current treatment consists of surgical resection, aggressive radiation and chemotherapy regimen. This therapeutic strategy had not changed since 2005 when the chemotherapy Temozolomide was approved. This therapeutic approach extended GBM patients’ life expectancy to approximately 15 months since diagnosis. Although recent progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, the majority of these leading drug candidates remain ineffective. Therefore, novel and effective treatment to GBM presents an unmet need. Lipid nanoparticles (LNPs) are the most clinically advanced delivery platform to date for systemic administration of RNA therapeutics, with the recent approval of Patisiran, siRNA encapsulating LNPs. In recent years, several gene editing technologies have been discovered in bacteria, enabling precise and permanent manipulations at the DNA level. The most advanced and versatile system is based on the CRISPR nuclease Cas9. The recognition of its target chromosomal DNA by Cas9 results in a site-specific double-strand break (DSB), that eventually results in gene disruption. This approach opens multiple venues for research and treatment of diseases including cancer. We have utilized CRISPR encapsulating LNPs to promote a therapeutic gene editing by disrupting key GBM survival genes in vitro in murine and human GBM cell lines as well as in vivo in an aggressive syngeneic GBM mouse model. Our results suggest that treatment with our LNPs based system can specifically and efficiently target GBM cells in vitro and in vivo. Our CRISPR-LNPs based platform could potentially mature to a clinical trial, and ultimately might become a new therapeutic modality in GBM.
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Shojaei, S., J. Alizadeh, J. Thliveris, N. Koleini, E. Kardami, G. M. Hatch, Fr Xu, S. Hombach-Klonisch, T. Klonisch, and S. Ghavami. "08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, S3 (June 2018): S1—S2. http://dx.doi.org/10.1017/cjn.2018.255.
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Glioblastoma multiforme (GBM) is the deadliest brain tumor with an approximate 14 month survival rate after diagnosis and treatment. Temozolomide (TMZ), the chemotherapeutic drug of choice for GBM, is an alkylating agent that causes DNA damage. TMZ treatment results in the induction of apoptosis in GBM cells, however, it induces autophagy and consequently chemoresistance. Statins are mevalonate (MEV) cascade inhibitors with beneficial effects on the enhancement of the survival rate of patients with different types of cancer. Here, we determined the effect of simvastatin (Simva), a blood brain barrier permeable statin, on the sensitization of GBM cells to TMZ induced apoptosis through inhibition of autophagy flux. We pretreated two GMB cell lines, U251 and U87 cells, with low doses of Simva (1 and 2.5 M, respectively) with or without different intermediates of the mevalonate cascade and then treated cells with TMZ (100 M) for 48-96 hrs. A signficiantly reduced viability and increased in the population of apoptotic dead cells were observed in GBM cells treated with the Simva-TMZ compared to cells treated with TMZ alone. Addition of MEV, Farnesyl pyrophosphate, Geranylgeranyl pyrophosphate and cholesterol did not attenuate these effects significantly. Sima-TMZ treatment did not alter the total cholesterol pool in U87 and U251 cells compared to controls. Western blot analysis, immunocytochemistry and transmission electron microscopy revealed that Simva-TMZ inhibited autophagic flux. Overall, the results suggest that sensitization of GBM cells to TMZ-induced apoptosis by Simva is independent on the cholesterol biosynthetic pathway but may involve inhibition of autophagy.
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Han, Sola, and Hae Sun Suh. "Impact of Integrating Machine Learning in Comparative Effectiveness Research of Oral Anticoagulants in Patients with Atrial Fibrillation." International Journal of Environmental Research and Public Health 19, no. 19 (October 9, 2022): 12916. http://dx.doi.org/10.3390/ijerph191912916.
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We aimed to compare the ability to balance baseline covariates and explore the impact of residual confounding between conventional and machine learning approaches to derive propensity scores (PS). The Health Insurance Review and Assessment Service database (January 2012–September 2019) was used. Patients with atrial fibrillation (AF) who initiated oral anticoagulants during July 2015–September 2018 were included. The outcome of interest was stroke/systemic embolism. To estimate PS, we used a logistic regression model (i.e., a conventional approach) and a generalized boosted model (GBM) which is a machine learning approach. Both PS matching and inverse probability of treatment weighting were performed. To evaluate balance achievement, standardized differences, p-values, and boxplots were used. To explore residual confounding, E-values and negative control outcomes were used. In total, 129,434 patients were identified. Although all baseline covariates were well balanced, the distribution of continuous variables seemed more similar when GBM was applied. E-values ranged between 1.75 and 2.70 and were generally higher in GBM. In the negative control outcome analysis, slightly more nonsignificant hazard ratios were observed in GBM. We showed GBM provided a better ability to balance covariates and had a lower impact of residual confounding, compared with the conventional approach in the empirical example of comparative effectiveness analysis.
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Jin, Dan, Son Le, Mathew Sebastian, Dongjiang Chen, Linchun Jin, and David Tran. "IMMU-46. ARTIFICIAL INTELLIGENCE-DIRECTED, GENE THERAPY-BASED TRANSDIFFERENTIATION OF GLIOBLASTOMA TO FUNCTIONAL DENDRITIC CELLS AS NOVEL CANCER IMMUNOTHERAPY." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi103. http://dx.doi.org/10.1093/neuonc/noab196.405.
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Abstract BACKGROUND Despite recent advances in tumor immunotherapy in solid tumors, success in GBM remains elusive, likely due to its poor immunogenicity and CNS barriers limiting immune cell trafficking. Here we describe a novel approach of stimulating glioma-specific immunity by transdifferentiating GBM cells in situ to induced dendritic cells (iDCs). METHODS We applied NETZEN, an integrated deep-learning and gene network-based ranking computational platform and identified cell fate determinants (CFDs) to convert GBM cells to DCs. CFDs were delivered using a viral vector. Transdifferentiation was assessed by immunophenotyping and iDCs functionally validated by their ability to prime naive T cells. RESULTS A four CFDs subnetwork anchored by PU.1 was sufficient to transdifferentiate mouse GBM cells to CD45+MHCII+ cells with high co-stimulatory CD80 expression and to induce nearly 98% of GBM cells to express 100-fold higher levels of MHCI. Consistent with a new identity of antigen-presenting cells (APC), the induced immune cells are growth arrested, exhibit 3-fold higher phagocytic activity and upregulate the canonical antigen processing and presenting machineries by 10-40 folds, resulting in 40-fold greater efficiency at processing ovalbumin and presenting SIINFEKL on MHCI compared to native GBM cells. Importantly, SIINFEKL-loaded iAPCs are capable of activating naive OTII-CD4+ and OTI-CD8+ T cells, indicating that they are DC-like. In addition, iDCs efficiently present tumor cell-intrinsic antigens and elicit >20-fold higher activation and cytotoxicity in tumor-specific T cells compared to native GBM cells. Lastly, intratumoral GBM-DC transdifferentiation in a syngeneic orthotopic GBM model produces a robust memory T cell response in deep cervical draining lymph nodes compared to control animals. CONCLUSIONS Our results comfirm that GBM-derived iDCs acquire functions similar to native DCs, and thus, lay the foundation for a novel therapeutic approach in which poorly immunogenic tumors like GBM may be forced to generate their own immunity from within through cell fate transdifferentiation.
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Antonica, Francesco, Francesca Garilli, Maria Del Mar Gardeazabal Bataller, Lucia Santomaso, and Luca Tiberi. "TMOD-06. MODELLING ADULT AND PAEDIATRIC GLIOBLASTOMA MULTIFORME (GBM) USING A GENE SCREEN-BASED APPROACH IN MICE AND HUMAN IPSC-DERIVED CEREBRAL ORGANOIDS." Neuro-Oncology 21, Supplement_6 (November 2019): vi263. http://dx.doi.org/10.1093/neuonc/noz175.1105.
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Abstract Glioblastoma multiforme (GBM) represent the most devastating form of high-grade glioma (HGG) affecting adults and children. Despite a multi-therapeutic approach consisting in surgery, radio- and chemo-therapy the prognosis remains poor. Several models such as xenograft, animal models and recently organoids, have been developed in order to investigate the physiopathology of GBM. Although several mouse models (where either gain- or loss-of function of genes/pathway found altered in patients induce tumour formation) have been generated many aspects of how the tumour is formed, evolves, infiltrates and recurs after treatments remain unclear. Another challenge is the creation of proper GBM models showing intratumor heterogeneity found in the patient tumour but missing in the animal model generated so far. To overcome the lack of that human tumour characteristic, we decided to generate new model of GBM using a gene screen-based approach in mice. Firstly, we analysed the genes found amplified or mutated in GBM patients; secondly, we over-expressed the candidate genes (combination of multiple genes found to be mutated or amplified in specific GBM patients) in the subventricular zone (SVZ) of P2 mouse brain. Thirdly, we analysed the formation of tumour after 2 months. We over-expressed roughly 50 combinations in newborn mice and found that only 3 successfully led to the formation of lesions positive for proliferation and brain tumour marker (i.e. GFAP). We are currently characterising the tumours by DNA methylation analysis and RNA-seq (for further confirmation of the cancer subtype and intratumor heterogeneity) or investigating the cell of origin of the tumour. Moreover, we are testing the tumorigenicity of specific in GBM-amplified/mutated gene combinations in hiPSC-derived cerebal organoids. Our data suggest that a gene screen-based approach can be used for quickly and easily assaying the tumorigenicity of genes found amplified/mutated in GBM patients as well as the biology behind such complex process.
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Tilak, Manali, Jennifer Holborn, Laura A. New, Jasmin Lalonde, and Nina Jones. "Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme." International Journal of Molecular Sciences 22, no. 4 (February 12, 2021): 1831. http://dx.doi.org/10.3390/ijms22041831.
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Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited response to existing therapies and eventually developing resistance to these interventions. As such, there is intense interest in better understanding the molecular alterations in GBM to guide the development of more efficient targeted therapies. GBM tumors can be classified into several molecular subtypes which have distinct genetic signatures, and they show aberrant activation of numerous signal transduction pathways, particularly those connected to receptor tyrosine kinases (RTKs) which control glioma cell growth, survival, migration, invasion, and angiogenesis. There are also non-canonical modes of RTK signaling found in GBM, which involve G-protein-coupled receptors and calcium channels. This review uses The Cancer Genome Atlas (TCGA) GBM dataset in combination with a data-mining approach to summarize disease characteristics, with a focus on select molecular pathways that drive GBM pathogenesis. We also present a unique genomic survey of RTKs that are frequently altered in GBM subtypes, as well as catalog the GBM disease association scores for all RTKs. Lastly, we discuss current RTK targeted therapies and highlight emerging directions in GBM research.
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Hsia, Tiffaney, Anudeep Yekula, Syeda M. Batool, Bob S. Carter, and Leonora Balaj. "Abstract 5175: Novel approach for glioblastoma characterization via tumor specific extracellular vesicles." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5175. http://dx.doi.org/10.1158/1538-7445.am2022-5175.
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Abstract INTRODUCTION: The utility of photosensitizers (PS), such as 5-Aminolevulinic acid (5-ALA), has been limited to fluorescence-guided surgery (FGS) and photodynamic therapy. The downstream metabolism of 5-ALA results in tumor-specific, highly selective accumulation of PpIX, an endogenous porphyrin, in tumor cells. We have previously reported evidence of PpIX in EVs derived from the plasma of glioblastoma (GBM) patients. Here, we characterize the tumor-specific nature of PpIX fluorescent EVs through quantification of their cargo, demonstrating their utility in the advancement of liquid biopsy for GBM diagnosis and management. METHODS: Fluorescence activated cell sorting was adapted for nanoparticle isolation and PpIX fluorescent EVs were sorted from plasma collected from patients (N = 8) diagnosed with GBM, undergoing FGS. RNA cargo was extracted and quantified via low input RNA-Seq. Matching patient tumor and total plasma EVs along with healthy control plasma EVs (N = 8) were sequenced in parallel. SUMMARY: Through sequencing analysis, we have demonstrated a distinct landscape of long RNAs (mRNA and lncRNA) in PpIX EVs, with isolation of this EV population resulting in an enrichment of lncRNAs. Considering the emerging diagnostic and prognostic potential of lncRNAs in GBM, exploration of such EVs provides valuable insight into the pathobiology of the tumor of origin. On a broader scale, gene expression analysis of PpIX EV cargo demonstrates at least a ten-fold enrichment of genes that are otherwise buried in the heterogeneous plasma EV background. Furthermore, downstream KEGG orthological analysis of PpIX EV cargo has revealed alignment of 78% of the significant pathways to processes implicated in cancer development and progression. We have identified a panel of genes unique to PpIX EVs, and reflective of the native tumor, that are implicated in GBM pathogenesis including GREM1, MAP4K4, and STAG2. Validation via quantitative and digital PCR of total plasma EVs from patient and healthy cohorts (N = 10, respectively) have yielded similar expression levels, as reflected in sequencing gene expression. Isolation of PpIX EVs, however, insinuates enriched genetic detection. CONCLUSION: In summary, this preliminary cohort of GBM patients has demonstrated the utility of 5-ALA induced PpIX fluorescence outside of its original intentions: facilitating tumor-specific EV identification for the progression of liquid biopsy. These findings are an inviting breakthrough in the development of individualized disease detection and monitoring. Citation Format: Tiffaney Hsia, Anudeep Yekula, Syeda M. Batool, Bob S. Carter, Leonora Balaj. Novel approach for glioblastoma characterization via tumor specific extracellular vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5175.
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Toussaint, Magali, Winnie Deuther-Conrad, Mathias Kranz, Steffen Fischer, Friedrich-Alexander Ludwig, Tareq A. Juratli, Marianne Patt, et al. "Sigma-1 Receptor Positron Emission Tomography: A New Molecular Imaging Approach Using (S)-(−)-[18F]Fluspidine in Glioblastoma." Molecules 25, no. 9 (May 6, 2020): 2170. http://dx.doi.org/10.3390/molecules25092170.
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Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (S)-(−)-[18F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical KD values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology.
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Tea, Melinda N., Santosh I. Poonnoose, and Stuart M. Pitson. "Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma." Cancers 12, no. 1 (January 1, 2020): 111. http://dx.doi.org/10.3390/cancers12010111.
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Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.
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Gu, Qiu-hua, Megan Huynh, Yue Shi, Xiao-yu Jia, Jie-jian Luo, Tai-jiao Jiang, Zhao Cui, Joshua D. Ooi, A. Richard Kitching, and Ming-hui Zhao. "Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces." Journal of the American Society of Nephrology 31, no. 6 (May 22, 2020): 1282–95. http://dx.doi.org/10.1681/asn.2019060619.
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BackgroundAntiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127–148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected.MethodsTo investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity.ResultsOn the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127–148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127–148. B7 induced T cell activation from human α3127–148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7’s pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135–145-immunized mice.ConclusionsSera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.
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Miller, C. Ryan, and Arie Perry. "Glioblastoma." Archives of Pathology & Laboratory Medicine 131, no. 3 (March 1, 2007): 397–406. http://dx.doi.org/10.5858/2007-131-397-g.
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Abstract Context.—Glioblastoma (GBM), the most common primary intracranial malignancy, is a morphologically diverse neoplasm with dismal prognosis despite multimodality therapy. Only 3 distinct morphologic variants of GBM are currently recognized by the current World Health Organization classification scheme, including GBM, giant cell GBM, and gliosarcoma. Additional variants, some of which have significant morphologic overlap with tumors that have more favorable prognosis and treatment response rates, particularly anaplastic oligodendroglioma, have been described since its publication in 2000 and may be included in the next classification. Objective.—To summarize the morphologic and molecular genetic diversity of both well-established and novel GBM variants and outline our approach to these heterogeneous neoplasms and their distinction from other diffuse, high-grade gliomas. Data Sources.—Published literature and our own experience in an active academic diagnostic surgical neuropathology practice were reviewed. Conclusions.—Precise subclassification of GBM is required for accurate prognostication and appropriate treatment planning.
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da Silva, Bárbara, Ryan K. Mathew, Euan S. Polson, Jennifer Williams, and Heiko Wurdak. "Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 8 (March 15, 2018): 862–68. http://dx.doi.org/10.1177/2472555218764623.
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Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. The high-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma, making complete surgical resection improbable. Modeling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs). The resulting formation of hybrid organoids demonstrated an invasive tumor phenotype that was distinct from noncancerous adult neural progenitor (NP) spheroid incorporation into eCOs. These findings provide a basis for the modeling and quantification of the GBM infiltration process using a stem-cell-based organoid approach, and may be used for the identification of anti-GBM invasion strategies.
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Lebel, A., V. Charest, P. Whitlock, D. Charest, and P. Morin. "P.038 Investigating the role of long non-coding RNAs in glioblastoma multiforme." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S26. http://dx.doi.org/10.1017/cjn.2018.140.
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Background: Malignant gliomas are the most common and deadly brain tumors. Mean survival rate for a patient diagnosed with a glioblastoma multiforme (GBM) remains slightly over one year. Standard of care consists of treatment with temozolomide (TMZ) and radiotherapy. Recent work has highlighted functions of long non-coding RNAs (lncRNAs) in GBM progression and TMZ response even though the information regarding these newly discovered molecules is sparse. The overarching objective of this project was thus to assess the expression of select lncRNAs in GBM tumor samples and in models of TMZ resistance. Methods: A qRT-PCR-based approach was undertaken to measure six lncRNAs in 19 primary GBM samples, four GBM cell lines and in-house developed TMZ-resistant GBM cells. Results: Elevated levels of Hotair and H19 were observed in primary GBM tumors while decreased expression of MEG3 was recorded in the same samples. Interestingly, levels of PANDA increased 3.4-fold in GBM cells resistant to TMZ when compared with their sensitive counterparts. Conclusions: Overall, this work provides evidence of lncRNA deregulation in GBM tumors and reveals a previously unexplored lncRNA potentially involved in TMZ resistance. Modulation of lncRNA targets via RNAi-mediated approaches is envisioned to clarify their function and to strengthen their position as therapeutic options in GBMs.
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Tomei, Sara, Andrea Volontè, Shilpa Ravindran, Stefania Mazzoleni, Ena Wang, Rossella Galli, and Cristina Maccalli. "MicroRNA Expression Profile Distinguishes Glioblastoma Stem Cells from Differentiated Tumor Cells." Journal of Personalized Medicine 11, no. 4 (April 1, 2021): 264. http://dx.doi.org/10.3390/jpm11040264.
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Glioblastoma (GBM) represents the most common and aggressive tumor of the brain. Despite the fact that several studies have recently addressed the molecular mechanisms underlying the disease, its etiology and pathogenesis are still poorly understood. GBM displays poor prognosis and its resistance to common therapeutic approaches makes it a highly recurrent tumor. Several studies have identified a subpopulation of tumor cells, known as GBM cancer stem cells (CSCs) characterized by the ability of self-renewal, tumor initiation and propagation. GBM CSCs have been shown to survive GBM chemotherapy and radiotherapy. Thus, targeting CSCs represents a promising approach to treat GBM. Recent evidence has shown that GBM is characterized by a dysregulated expression of microRNA (miRNAs). In this study we have investigated the difference between human GBM CSCs and their paired autologous differentiated tumor cells. Array-based profiling and quantitative Real-Time PCR (qRT-PCR) were performed to identify miRNAs differentially expressed in CSCs. The Cancer Genome Atlas (TCGA) data were also interrogated, and functional interpretation analysis was performed. We have identified 14 miRNAs significantly differentially expressed in GBM CSCs (p < 0.005). MiR-21 and miR-95 were among the most significantly deregulated miRNAs, and their expression was also associated to patient survival. We believe that the data provided here carry important implications for future studies aiming at elucidating the molecular mechanisms underlying GBM.
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Brosch, Philippa K., Tessa Korsa, Danush Taban, Patrick Eiring, Sascha Hildebrand, Julia Neubauer, Heiko Zimmermann, et al. "Glucose and Inositol Transporters, SLC5A1 and SLC5A3, in Glioblastoma Cell Migration." Cancers 14, no. 23 (November 24, 2022): 5794. http://dx.doi.org/10.3390/cancers14235794.
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(1) Background: The recurrence of glioblastoma multiforme (GBM) is mainly due to invasion of the surrounding brain tissue, where organic solutes, including glucose and inositol, are abundant. Invasive cell migration has been linked to the aberrant expression of transmembrane solute-linked carriers (SLC). Here, we explore the role of glucose (SLC5A1) and inositol transporters (SLC5A3) in GBM cell migration. (2) Methods: Using immunofluorescence microscopy, we visualized the subcellular localization of SLC5A1 and SLC5A3 in two highly motile human GBM cell lines. We also employed wound-healing assays to examine the effect of SLC inhibition on GBM cell migration and examined the chemotactic potential of inositol. (3) Results: While GBM cell migration was significantly increased by extracellular inositol and glucose, it was strongly impaired by SLC transporter inhibition. In the GBM cell monolayers, both SLCs were exclusively detected in the migrating cells at the monolayer edge. In single GBM cells, both transporters were primarily localized at the leading edge of the lamellipodium. Interestingly, in GBM cells migrating via blebbing, SLC5A1 and SLC5A3 were predominantly detected in nascent and mature blebs, respectively. (4) Conclusion: We provide several lines of evidence for the involvement of SLC5A1 and SLC5A3 in GBM cell migration, thereby complementing the migration-associated transportome. Our findings suggest that SLC inhibition is a promising approach to GBM treatment.
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Martins, T. A., N. Tatari, M. Ritz, T. Shekarian, P. Schmassmann, D. Kaymak, and G. Hutter. "P06.03.A Combination of EGFRvIII CAR T cell therapy and paracrine GAM modulation for the treatment of GBM." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii38. http://dx.doi.org/10.1093/neuonc/noac174.127.
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Abstract Background The glioblastoma (GBM) immune microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). Previously, we showed that blockade of the don't-eat-me signal CD47, overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, CD47 blockade monotherapy has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local chimeric antigen receptor (CAR) T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM. Material and Methods We lentivirally transduced healthy donor human T cells to generate humanized EGFRvIII-directed CAR T that constitutively secrete a SIRPγ-related protein (SGRP) with high affinity to CD47. Killing assays were performed with endogenous EGFRvIII-expressing BS153 or EGFRvIII-overexpressed U251 GBM cells and assessed by Incucyte time-lapse imaging analysis. CAR T cell activation was confirmed by flow cytometry (FC) and IFNγ was detected from co-culture supernatants or mouse plasma by ELISA. The CAR T cell secretome was analyzed by liquid chromatography-mass spectrometry (LC-MS) to confirm the secretion of SGRP. NSG mice were orthotopically implanted with either EGFRvIII+ BS153 or U251 cells and treated intratumorally with one or two CAR T cell infusions. Results EGFRvIII and EGFRvIII-SGRP CAR T proliferated and killed tumor cells in vitro in a dose-dependent manner within 72h with complete cytotoxicity at E:T 1:1 compared to CD19 CAR T. CAR T cells specifically co-expressed CD25 and CD107a and secreted IFNγ in the presence of tumor antigen (24h CD25/CD107a co-expression: EGFRvIII=59.3±3.00%, EGFRvIII-SGRP=52.6±1.42%, CD19=0.1±0.07%; 24h IFNγ secretion: EGFRvIII=173.6±2.50%, EGFRvIII-SGRP=113.8±6.42%, CD19=4.5±1.49%). Differential expression analysis of the CAR T cell secretome identified SGRP in EGFRvIII-SGRP CAR T supernatants (-Log10qValue/Log2fold-change=13.72/6.62). Consistent with studies of systemic EGFRvIII CAR T cell therapy, our data suggest that intratumoral EGFRvIII CAR T were insufficient to eliminate BS153 tumors with endogenous EGFRvIII (Overall survival; EGFRvIII: 20%, CD19: 0%, n=5/group). Conclusion Here, we show that EGFRvIII CAR T specifically targeted and killed EGFRvIII+ GBM cells in vitro, but failed to control tumor growth in vivo without GAM modulation. EGFRvIII-SGRP CAR T secretome analysis identified SGRP from the supernatants of unstimulated monocultures. SGRP impaired the binding of SIRPα-Fc to CD47-upregulated GBM cells in vitro, but did not elicit macrophage-mediated phagocytosis of GBM cells in our current in vitro experimental setup. Future work will focus on the functional characterization of SGRP and on further investigating the additive effect of CAR T cell therapy and GAM modulation using translational in vivo and ex vivo models.
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Mecca, Carmen, Ileana Giambanco, Rosario Donato, and Cataldo Arcuri. "Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence." Disease Markers 2018 (December 18, 2018): 1–10. http://dx.doi.org/10.1155/2018/9230479.
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The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.
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Lucki, Natasha C., Genaro R. Villa, Naja Vergani, Michael J. Bollong, Brittney A. Beyer, Jae Wook Lee, Justin L. Anglin, et al. "A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer." Proceedings of the National Academy of Sciences 116, no. 13 (March 7, 2019): 6435–40. http://dx.doi.org/10.1073/pnas.1816626116.
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Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.
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Song, Zhuqing, Xiuxian Huang, Jieqiong Wang, Feiyan Cai, Ping Zhao, and Fei Yan. "Targeted Delivery of Liposomal Temozolomide Enhanced Anti-Glioblastoma Efficacy through Ultrasound-Mediated Blood–Brain Barrier Opening." Pharmaceutics 13, no. 8 (August 17, 2021): 1270. http://dx.doi.org/10.3390/pharmaceutics13081270.
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Glioblastoma (GBM) is the commonest form of primary brain tumor in the central nervous system, with median survival below 15 months and only a 25% two-year survival rate for patients. One of the major clinical challenges in treating GBM is the presence of the blood–brain barrier (BBB), which greatly limits the availability of therapeutic drugs to the tumor. Ultrasound-mediated BBB opening provides a promising approach to help deliver drugs to brain tumors. The use of temozolomide (TMZ) in the clinical treatment of GBM has been shown to be able to increase survival in patients with GBM, but this improvement is still trivial. In this study, we developed a liposomal temozolomide formulation (TMZ-lipo) and locally delivered these nanoparticles into GBM through ultrasound-mediated BBB opening technology, significantly suppressing tumor growth and prolonging tumor-bearing animal survival. No significant side effects were observed in comparison with control rats. Our study provides a novel strategy to improve the efficacy of TMZ against GBM.
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Zhao, Yi, Jae-Hyeok Kang, Ki-Chun Yoo, Seok-Gu Kang, Hae-June Lee, and Su-Jae Lee. "K-RAS Acts as a Critical Regulator of CD44 to Promote the Invasiveness and Stemness of GBM in Response to Ionizing Radiation." International Journal of Molecular Sciences 22, no. 20 (October 10, 2021): 10923. http://dx.doi.org/10.3390/ijms222010923.
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Radiation therapy is a current standard-of-care treatment and is used widely for GBM patients. However, radiation therapy still remains a significant barrier to getting a successful outcome due to the therapeutic resistance and tumor recurrence. Understanding the underlying mechanisms of this resistance and recurrence would provide an efficient approach for improving the therapy for GBM treatment. Here, we identified a regulatory mechanism of CD44 which induces infiltration and mesenchymal shift of GBM. Ionizing radiation (IR)-induced K-RAS/ERK signaling activation elevates CD44 expression through downregulation of miR-202 and miR-185 expression. High expression of CD44 promotes SRC activation to induce cancer stemness and EMT features of GBM cells. In this study, we demonstrate that the K-RAS/ERK/CD44 axis is a key mechanism in regulating mesenchymal shift of GBM cells after irradiation. These findings suggest that blocking the K-RAS activation or CD44 expression could provide an efficient way for GBM treatment.
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D’Alessandro, Giuseppina, Lucia Monaco, Luigi Catacuzzeno, Fabrizio Antonangeli, Antonio Santoro, Vincenzo Esposito, Fabio Franciolini, Heike Wulff, and Cristina Limatola. "Radiation Increases Functional KCa3.1 Expression and Invasiveness in Glioblastoma." Cancers 11, no. 3 (February 26, 2019): 279. http://dx.doi.org/10.3390/cancers11030279.
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Glioblastoma (GBM) is a deadly brain tumor, with fast recurrence even after surgical intervention, radio- and chemotherapies. One of the reasons for relapse is the early invasion of surrounding brain parenchyma by GBM, rendering tumor eradication difficult. Recent studies demonstrate that, in addition to eliminate possible residual tumoral cells after surgery, radiation stimulates the infiltrative behavior of GBM cells. The intermediate conductance of Ca2+-activated potassium channels (KCa3.1) play an important role in regulating the migration of GBM. Here, we show that high dose radiation of patient-derived GBM cells increases their invasion, and induces the transcription of key genes related to these functions, including the IL-4/IL-4R pair. In addition, we demonstrate that radiation increases the expression of KCa3.1 channels, and that their pharmacological inhibition counteracts the pro-invasive phenotype induced by radiation in tumor cells. Our data describe a possible approach to treat tumor resistance that follows radiation therapy in GBM patients.
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Morrow, Danielle, Nicholas Bayley, Kevin Williams, Hayato Muranaka, Robert Prins, Linda Liau, Timothy Cloughesy, Steven Bensinger, and David Nathanson. "CBMT-43. INTEGRATED LIPIDOMIC AND MOLECULAR ANALYSIS REVEALS A SUBSET OF GLIOBLASTOMA VULNERABLE TO FERROPTOSIS." Neuro-Oncology 21, Supplement_6 (November 2019): vi42. http://dx.doi.org/10.1093/neuonc/noz175.165.
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Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of a library of molecularly diverse patient-derived GBM cells (n=30). Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Polyunsaturated fatty acids (PUFAs) were among the most significant lipids that distinguished these two groups of GBM tumors. Intriguingly, this lipid metabolic phenotype was associated with heightened sensitivity to ferroptosis – a newly discovered form of regulated cell death. As PUFA oxidation is a critical feature of ferroptosis, our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and ferroptosis. This relationship may present a new therapeutic opportunity to target ferroptosis in a molecularly-defined subset of GBMs.
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Panovska, Dena, Asier Antoranz, Pieter-Jan Creemers, Marleen Derweduwe, Pouya Nasari, Gabriele Orlando, Sofie Van Gassen, et al. "EXTH-20. SINGLE-CELL DRUG ACTIVITY MAPPING IN GLIOBLASTOMA IDENTIFIES EXTENDED DRUG RESPONSE HETEROGENEITY AND THERAPY-INDUCED CELLULAR PLASTICITY." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi167. http://dx.doi.org/10.1093/neuonc/noab196.659.
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Abstract Glioblastoma (GBM) remains a highly malignant and incurable brain tumour. The inability to achieve clinical improvements in GBM treatment can be attributed to the excessive heterogeneity and plasticity of GBM cells, which is reflected by the presence of various cellular states within each tumour. How each of these tumour cell subtypes respond to therapy remains largely unknown. In this work, we developed a functional diagnostic analysis pipeline to measure therapeutic activity in GBM tumour cells at single-cell resolution using mass cytometry by time-of-flight (CyTOF). By applying an optimised GBM-specific and therapy-tailored antibody panel, we measured therapeutic activity upon exposure to ionising radiation (RT) or a small molecule MDM2 inhibitor (AMG232) in a cohort of patient-derived GBM cell lines (n=14). As such, extended heterogeneity in drug responsiveness was reflected by diverse degrees of alterations in cell cycle progression and apoptotic signalling, in addition to shifts in tumoral phenotypic states implying therapy-induced plasticity. A similar approach was used to measure drug activity in freshly resected tumour samples (n=18) harvested from different tumour regions (core or invasive front) within hours following surgery. Accordingly, we identified highly variable fractions of responsive tumour and microenvironmental cell populations in a patient-specific way. The ability to measure drug activity at single-cell resolution in a patient-tailored manner by applying a genotype-agnostic method, paves the way for advanced precision cancer medicine in GBM by offering a novel approach to more precisely select eligible patients for prospective clinical trials.