bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021–04–11
seven papers selected by
Oltea Sampetrean, Keio University
  1. Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.
  2. Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond.
  3. Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas.
  4. MGMT promoter methylation is associated with patient age and 1p/19q status in IDH-mutant gliomas.
  5. Erratum to: STEM-19. RESISTANCE IS FUTILE: UNDERSTANDING AND TARGETING THE CDK5-CREB1-MCL1 AXIS TO PREVENT RADIATION RESISTANCE IN GLIOMA STEM CELLS.
  6. C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells.
  7. Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma.
  1. Sci Rep. 2021 Apr 07. 11(1): 7632
    Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.
    Shiliang Huang, Joel E Michalek, David A Reardon, Patrick Y Wen, John R Floyd, Peter T Fox, Geoffrey D Clarke, Paul A Jerabek, Kathleen M Schmainda, Mark Muzi, Hyewon Hyun, Eudocia Quant Lee, Andrew J Brenner.
      Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.
    DOI:  https://doi.org/10.1038/s41598-021-84331-5
  2. Front Oncol. 2021 ;11 612354
    Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond.
    Michael Orth, Valerie Albrecht, Karin Seidl, Linda Kinzel, Kristian Unger, Julia Hess, Lisa Kreutzer, Na Sun, Benjamin Stegen, Alexander Nieto, Jessica Maas, Nicolas Winssinger, Anna A Friedl, Axel K Walch, Claus Belka, Horst Zitzelsberger, Maximilian Niyazi, Kirsten Lauber.
      Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with per se limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells in vitro. In vivo, HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising in vitro results the in vivo efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences.
    Keywords:  HSP90 inhibition; HSP90i; NW457; glioblastoma; hypermigration; radiosensitization; radiotherapy
    DOI:  https://doi.org/10.3389/fonc.2021.612354
  3. Neuro Oncol. 2021 Apr 05. pii: noab081. [Epub ahead of print]
    Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas.
    Yao Yu, Javier Villanueva-Meyer, Matthew R Grimmer, Stephanie Hilz, David A Solomon, Serah Choi, Michael Wahl, Tali Mazor, Chibo Hong, Anny Shai, Joanna J Phillips, Bruce H Wainer, Michael McDermott, Daphne Haas-Kogan, Jennie W Taylor, Nicholas Butowski, Jennifer L Clarke, Mitchel S Berger, Annette M Molinaro, Susan M Chang, Joseph F Costello, Nancy Ann Oberheim Bush.
       BACKGROUND: Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas, but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.
    METHODS: We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent re-operation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.
    RESULTS: Hypermutation was associated with high-grade disease at the time of re-operation (OR 12.0 95% CI 2.5-115.5, p=0.002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, p=0.024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (p=0.003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. 8-year transformation-free survival was 53.8% (95% CI 42.8-69.2) and 61% of analyzed transformed cases were HM.
    CONCLUSIONS: TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ, and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.
    Keywords:  Hypermutation; IDH-mutant; Low-Grade Glioma; Temozolomide; Tumor Mutational Burden
    DOI:  https://doi.org/10.1093/neuonc/noab081
  4. Neuro Oncol. 2021 Apr 08. pii: noab039. [Epub ahead of print]
    MGMT promoter methylation is associated with patient age and 1p/19q status in IDH-mutant gliomas.
    Craig Horbinski, Kathleen McCortney, Roger Stupp.
      
    DOI:  https://doi.org/10.1093/neuonc/noab039
  5. Neuro Oncol. 2021 Apr 07. pii: noab070. [Epub ahead of print]
    Erratum to: STEM-19. RESISTANCE IS FUTILE: UNDERSTANDING AND TARGETING THE CDK5-CREB1-MCL1 AXIS TO PREVENT RADIATION RESISTANCE IN GLIOMA STEM CELLS.
    Subhas Mukherjee, Cheryl Olson, Bilge Dundar, Nitya Sharma, Steven Markwell, Daniel Brat.
      
    DOI:  https://doi.org/10.1093/neuonc/noab070
  6. Cell Death Dis. 2021 Apr 06. 12(4): 348
    C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells.
    Sara Manzano, Alvaro Gutierrez-Uzquiza, Paloma Bragado, Celia Sequera, Óscar Herranz, María Rodrigo-Faus, Patricia Jauregui, Stephanie Morgner, Ignacio Rubio, Carmen Guerrero, Almudena Porras.
      Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remains unknown. Database analyses revealed a reduced C3G mRNA expression in GBM patient samples. C3G protein levels were also decreased in a panel of human GBM cell lines as compared to astrocytes. Based on this, we characterized C3G function in GBM using in vitro and in vivo human GBM models. We report here that C3G downregulation promoted the acquisition of a more mesenchymal phenotype that enhanced the migratory and invasive capacity of GBM cells. This facilitates foci formation in anchorage-dependent and -independent growth assays and the generation of larger tumors in xenografts and chick chorioallantoic membrane (CAM) assays, but with a lower cell density, as proliferation was reduced. Mechanistically, C3G knock-down impairs EGFR signaling by reducing cell surface EGFR through recycling inhibition, while upregulating the activation of several other receptor tyrosine kinases (RTKs) that might promote invasion. In particular, FGF2, likely acting through FGFR1, promoted invasion of C3G-silenced GBM cells. Moreover, ERKs mediate this invasiveness, both in response to FGF2- and serum-induced chemoattraction. In conclusion, our data show the distinct dependency of GBM tumors on C3G for EGF/EGFR signaling versus other RTKs, suggesting that assessing C3G levels may discriminate GBM patient responders to different RTK inhibition protocols. Hence, patients with a low C3G expression might not respond to EGFR inhibitors.
    DOI:  https://doi.org/10.1038/s41419-021-03631-w
  7. Cell Death Dis. 2021 Apr 07. 12(4): 374
    Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma.
    Seung Won Choi, Yeri Lee, Kayoung Shin, Harim Koo, Donggeon Kim, Jason K Sa, Hee Jin Cho, Hye-Mi Shin, Se Jeong Lee, Hyunho Kim, Seok Chung, Jihye Shin, Cheolju Lee, Do-Hyun Nam.
      PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes ('edge mutations') localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations ('edge mutations') in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-021-03657-0
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