bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021‒08‒15
seventeen papers selected by
Oltea Sampetrean
Keio University

  1. Cancer Discov. 2020 Feb;10(2): 173
      Outer radial glia (oRG)-like glioma stem cells (GSC) were enriched in human glioblastomas.
  2. Cancer Discov. 2020 Feb;10(2): 175
      CD73hi macrophages are enriched in glioblastoma and may contribute to immunotherapy resistance.
  3. Pharmaceutics. 2021 Jul 09. pii: 1053. [Epub ahead of print]13(7):
      Gliomas are the most common type of brain tumor that occur in adults and children. Glioblastoma multiforme (GBM) is the most common, aggressive form of brain cancer in adults and is universally fatal. The current standard-of-care options for GBM include surgical resection, radiotherapy, and concomitant and/or adjuvant chemotherapy. One of the major challenges that impedes success of chemotherapy is the presence of the blood-brain barrier (BBB). Because of the tightly regulated BBB, immune surveillance in the central nervous system (CNS) is poor, contributing to unregulated glioma cell growth. This review gives a comprehensive overview of the latest advances in treatment of GBM with emphasis on the significant advances in immunotherapy and novel therapeutic delivery strategies to enhance treatment for GBM.
    Keywords:  blood–brain barrier (BBB); blood–brain tumor barrier (BBTB); chemotherapy; focused ultrasound (FUS); glioblastoma; hydrogels; immune checkpoint inhibitors (ICIs); radiation; smart hydrogels; stem cell engineering; stem cell-based therapy; surgery
  4. Transl Oncol. 2021 Aug 05. pii: S1936-5233(21)00184-4. [Epub ahead of print]14(11): 101192
      An important factor correlated with poor survival in glioblastoma (GBM) is the aberrant and persistent activation of STAT3, a critical transcription factor that regulates multiple genes with key roles in cell survival, proliferation, resistance to chemotherapy, and stem cell maintenance. The Interleukin-6 (IL6)-STAT3 signaling axis has been studied extensively in inflammation and cancer. However, it is not completely understood how high levels of activated STAT3 are sustained in tumors. Previously, we identified a novel mechanism of biphasic activation of STAT3 in response to gp130-linked cytokines, including IL6, in which activation of STAT3 is prolonged by circumventing the negative regulatory mechanisms induced by its initial activationTo target prolonged STAT3 activation, we used the small molecule inhibitor bazedoxifene (BZA), which blocks formation of the IL6 receptor-gp130 complex. Glioma stem-like cells (GSCs) are more tumorigenic and more resistant to therapy. STAT3 is a key driver of the expression of stem cell transcription factors, making it a therapeutically important target in GBM. We show that treating GSCs with BZA decreases their self-renewal capacity and the expression of GSC markers in vitro. Additionally, BZA crosses the blood-brain barrier and confers a survival advantage in an orthotopic syngeneic mouse model of GBM. Although IL6-STAT3 signaling is important for GSC survival, a therapeutic agent that inhibits this pathway without toxicity has yet to be identified. Our findings reveal a mechanism of sustained STAT3 signaling in GBM and reveal its role in GSC maintenance, and we identify BZA as a novel candidate for treating GBM.
    Keywords:  Bazedoxifene; Cancer stem cells; Glioblastoma; Glioma stem cells; IL6; STAT3
  5. Cancer Discov. 2020 Aug;10(8): OF6
      Ivosidenib, an inhibitor of mutant IDH1, was safe and showed early evidence of efficacy in glioma.
  6. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab075
      Background: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide-version 3-(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3.Methods: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3-4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle.
    Results: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%.
    Conclusions: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.
    Keywords:  chemotherapy; clinical trial ; drug repurposing; glioblastoma; multi-drug combination
  7. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab076
      Background: The radio- and chemo-resistance of glioblastoma stem-like cells (GSCs), together with their innate tumor-initiating aptitude, make this cell population a crucial target for effective therapies. However, targeting GSCs is hardly difficult and complex, due to the presence of the blood-brain barrier (BBB) and the infiltrative nature of GSCs arousing their dispersion within the brain parenchyma.Methods: Liposomes (LIPs), surface-decorated with an Apolipoprotein E-modified peptide (mApoE) to enable BBB crossing, were loaded with doxorubicin (DOXO), as paradigm of cytotoxic drug triggering immunogenic cell death (ICD). Patient-derived xenografts (PDXs) obtained by GSC intracranial injection were treated with mApoE-DOXO-LIPs alone or concomitantly with radiation.
    Results: Our results indicated that mApoE, through the engagement of the low-density lipoprotein receptor (LDLR), promotes mApoE-DOXO-LIPs transcytosis across the BBB and confers target specificity towards GSCs. Irradiation enhanced LDLR expression on both BBB and GSCs, thus further promoting LIP diffusion and specificity. When administered in combination with radiations, mApoE-DOXO-LIPs caused a significant reduction of in vivo tumor growth due to GSC apoptosis. GSC apoptosis prompted microglia/macrophage phagocytic activity, together with the activation of the antigen-presenting machinery crucially required for anti-tumor adaptive immune response.
    Conclusions: Our results advocate for radiotherapy and adjuvant administration of drug-loaded, mApoE-targeted nanovectors as an effective strategy to deliver cytotoxic molecules to GSCs at the surgical tumor margins, the forefront of glioblastoma (GBM) recurrence, circumventing BBB hurdles. DOXO encapsulation proved in situ immune response activation within GBM microenvironment.
    Keywords:  blood–brain barrier; drug-loaded liposomes; glioblastoma stem cell; immunogenic cell death; radiotherapy
  8. Cell Death Dis. 2021 Aug 11. 12(8): 785
      Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram's anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.
  9. Sci Rep. 2021 Aug 10. 11(1): 16196
      We have previously shown that the transmembrane protein ODZ1 serves for glioblastoma (GBM) cells to invade the surrounding tissue through activation of RhoA/ROCK pathway. However, the transcriptional machinery used by GBM cells to regulate the expression of ODZ1 is unknown. Here we show that interaction with tumor microenvironment elements, mainly activated monocytes through IL-6 secretion, and the extracellular matrix protein fibronectin, induces the Stat3 transcriptional pathway and upregulates ODZ1 which results in GBM cell migration. This signaling route is abrogated by blocking the IL-6 receptor, inhibiting Jak kinases or knocking down Stat3. Furthermore, we have identified a Stat3 responsive element in the ODZ1 gene promoter, about 1 kb from the transcription start site. Luciferase-reporter assays confirmed that the promoter responds to the presence of monocytic cells and this activation is greatly reduced when the Stat3 site is mutated or following treatment with a neutralizing anti-IL-6 receptor antibody or transfecting GBM cells with a dominant negative variant of Stat3. Overall, we show that monocyte-secreted IL-6 and the extracellular matrix protein fibronectin activate the axis Stat3-ODZ1 and promote migration of GBM cells. This is the first described transcriptional mechanism used by tumor cells to promote the expression of the invasion factor ODZ1.
  10. Pharmaceutics. 2021 Jul 16. pii: 1091. [Epub ahead of print]13(7):
      The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice.METHODS: Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times.
    RESULTS: In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle.
    CONCLUSIONS: These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment.
    Keywords:  Rho GTPase; brain tumor; chronopharmacology; glioma
  11. Cancer Cell. 2021 Aug 09. pii: S1535-6108(21)00387-1. [Epub ahead of print]39(8): 1056-1058
      In a recent issue of Nature, Pan and colleagues explore whether light-induced stimulation of the optic nerve could influence the biology of optic gliomas. This study highlights the importance of neuronal-glioma interactions.
  12. Neuro Oncol. 2021 Aug 12. pii: noab197. [Epub ahead of print]
      BACKGROUND: Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy.METHODS: Patient derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee-1 inhibitor, and tissue drug distribution was measured with MALDI MSI. Phosphoproteomics was measured in the same tumors to identify biomarkers of drug target engagement and cellular adaptive response. Multiplexed tissue imaging was performed on sister sections to evaluate spatial co-localization of drug and cellular response. The integrated platform was then applied on clinical specimens from glioblastoma patients enrolled in a Phase 1 clinical trial.
    RESULTS: PDX tumors exposed to different doses of adavosertib revealed intra and inter-tumoral heterogeneity of drug distribution and integration of the heterogeneous drug distribution with phosphoproteomics and multiplexed tissue imaging revealed new markers of molecular response to adavosertib. Analysis of paired clinical specimens from patients enrolled in the Phase 1 clinical trial informed the translational potential of the identified biomarkers in studying patient's response to adavosertib.
    CONCLUSIONS: The multimodal platform identified a signature of drug efficacy and patient-specific adaptive responses applicable to pre-clinical and clinical drug development. The information generated by the approach may inform mechanisms of success and failure in future early phase clinical trials, providing information for optimizing clinical trial design and guiding future application into clinical practice.
    Keywords:  Drug distribution; drug response; mass spectrometry imaging; phosphoproteomics; t-CyCIF
  13. Anal Bioanal Chem. 2021 Aug 09.
      Desorption electrospray ionization mass spectrometry (DESI-MS) is well suited for intraoperative tissue analysis since it requires little sample preparation and offers rapid and sensitive molecular diagnostics. Currently, intraoperative assessment of the tumor cell percentage of glioma biopsies can be made by measuring a single metabolite, N-acetylaspartate (NAA). The inclusion of additional biomarkers will likely improve the accuracy when distinguishing brain parenchyma from glioma by DESI-MS. To explore this possibility, mass spectra were recorded for extracts from 32 unmodified human brain samples with known pathology. Statistical analysis of data obtained from full-scan and multiple reaction monitoring (MRM) profiles identified discriminatory metabolites, namely gamma-aminobutyric acid (GABA), creatine, glutamic acid, carnitine, and hexane-1,2,3,4,5,6-hexol (abbreviated as hexol), as well as the established biomarker NAA. Brain parenchyma was readily differentiated from glioma based on these metabolites as measured both in full-scan mass spectra and by the intensities of their characteristic MRM transitions. New DESI-MS methods (5 min acquisition using full scans and MS/MS), developed to measure ion abundance ratios among these metabolites, were tested using smears of 29 brain samples. Ion abundance ratios based on signals for GABA, creatine, carnitine, and hexol all had sensitivities > 90%, specificities > 80%, and accuracies > 85%. Prospectively, the implementation of diagnostic ion abundance ratios should strengthen the discriminatory power of individual biomarkers and enhance method robustness against signal fluctuations, resulting in an improved DESI-MS method of glioma diagnosis.
    Keywords:  Ambient ionization; Biomarker; Glioma; Metabolomics; Multiple reaction monitoring; Tandem mass spectrometry
  14. Neuro Oncol. 2021 Aug 13. pii: noab199. [Epub ahead of print]
      BACKGROUND: Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States.METHODS: Incidence data from 2000-2017 were obtained from CBTRUS, which obtains data from the NPCR and SEER, and survival data from the CDC's NPCR Registries. Age-adjusted incidence rates and rate ratios (IRR) per 100,000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences.
    RESULTS: Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI:1.01 - 1.07, p=0.003), increasing with age, peaking at 50-59 years (IRR:1.56, 95% CI:1.53 - 1.59, p<0.001). Females had worse survival for ages 0-9 (HR:0.93, 95% CI:0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR:1.36, 95% CI:1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma.
    CONCLUSIONS: To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.
    Keywords:  CBTRUS; age; glioma; incidence; sex-differences; survival
  15. Exp Cell Res. 2021 Aug 04. pii: S0014-4827(21)00304-9. [Epub ahead of print] 112751
      Astrocytes are essential to brain homeostasis and their dysfunction can have devastating consequences on human quality of life. Such deleterious effects are generally due in part to changes that occur at the cellular level, which may be biochemical or biomechanical in nature. One biomechanical change that can occur is a change in tissue stiffness. Brain tumors are generally associated with increased brain tissue stiffness, but the impact increased tissue stiffness has on astrocyte biomechanical behavior is poorly understood. Therefore, in this study we cultured human astrocytes on flexible substrates with stiffness that mimicked the healthy human brain (1 kPa), meningioma (4 kPa), and glioma (11 kPa) and investigated astrocyte biomechanical behavior by measuring cell-substrate tractions, strain energies, cell-cell intercellular stresses, and cellular velocities. In general, tractions, intercellular stresses, and strain energy was observed to increase as a function of increased substrate stiffness, while cell velocities were observed to decrease with increased substrate stiffness. We believe this study will be of great importance to the fields of brain pathology and brain physiology.
    Keywords:  astrocytes; biomechanics; brain tumors; extracellular matrix; stiffness
  16. Cancer Discov. 2021 Aug 13. pii: candisc.0245.2021. [Epub ahead of print]
      While oncogenic mutations have been found in non-diseased, proliferative non-neural tissues, their prevalence in the human brain is unknown. Targeted sequencing of genes implicated in brain tumors in 418 samples derived from 110 individuals of varying ages, without tumor diagnoses, detected oncogenic somatic single-nucleotide variants (sSNVs) in 5.4% of the brains, including IDH1 R132H. These mutations were largely present in subcortical white matter and enriched in glial cells, and surprisingly, were less common in older individuals. A depletion of high-allele frequency sSNVs representing macroscopic clones with age was replicated by analysis of bulk RNAseq data from 1,816 non-diseased brain samples ranging from fetal to old age. We also describe large clonal copy number variants, and that sSNVs show mutational signatures resembling those found in gliomas, suggesting that mutational processes of the normal brain drive early glial oncogenesis. This study helps understand the origin and early evolution of brain tumors.