bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–02–18
seven papers selected by
Oltea Sampetrean, Keio University
  1. Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.
  2. Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
  3. Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.
  4. Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.
  5. Mechanistic insight into glioma through spatially multidimensional proteomics.
  6. Antigen Self-Presented Personalized Nanovaccines Boost the Immunotherapy of Highly Invasive and Metastatic Tumors.
  7. Cancer-associated fibroblast-secreted collagen is associated with immune inhibitor receptor LAIR1 in gliomas.
  1. Neuro Oncol. 2024 Feb 16. pii: noae028. [Epub ahead of print]
    Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.
    Hong Sheng Cheng, Yuk Kien Chong, Eldeen Kai Yi Lim, Xin Yi Lee, Qing You Pang, Wisna Novera, Charlie Marvalim, Jeannie Xue Ting Lee, Beng Ti Ang, Carol Tang, Nguan Soon Tan.
       BACKGROUND: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype.
    METHODS: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays and comet assays were used to examine the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells. The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis.
    RESULTS: Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favourably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintains temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts.
    CONCLUSION: Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.
    Keywords:  MAPK signaling; Precision medicine; brain cancer; glioma; targeted therapy
    DOI:  https://doi.org/10.1093/neuonc/noae028
  2. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2317343121
    Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
    Evan K Noch, Laura Palma, Isaiah Yim, Nayah Bullen, Daniel Barnett, Alexander Walsh, Bhavneet Bhinder, Elisa Benedetti, Jan Krumsiek, Justin Gurvitch, Sumaiyah Khwaja, Daphne Atlas, Olivier Elemento, Lewis C Cantley.
      Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.
    Keywords:  cysteine; glioblastoma; hydrogen peroxide; mitochondrial metabolism; reductive stress
    DOI:  https://doi.org/10.1073/pnas.2317343121
  3. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2306973121
    Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.
    Sergej Kudruk, Connor M Forsyth, Michelle Z Dion, Jenny K Hedlund Orbeck, Jingqin Luo, Robyn S Klein, Albert H Kim, Amy B Heimberger, Chad A Mirkin, Alexander H Stegh, Natalie Artzi.
      Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic.
    Keywords:  glioblastoma; immunotherapy; neuro-nanotechnology
    DOI:  https://doi.org/10.1073/pnas.2306973121
  4. Sci Transl Med. 2024 Feb 14. 16(734): eadj5962
    Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.
    Jiajia Chen, Daniel J Laverty, Surabhi Talele, Ashwin Bale, Brett L Carlson, Kendra A Porath, Katrina K Bakken, Danielle M Burgenske, Paul A Decker, Rachael A Vaubel, Jeanette E Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F Elmquist, Zachary D Nagel, Shiv K Gupta, Jann N Sarkaria.
      ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.
    DOI:  https://doi.org/10.1126/scitranslmed.adj5962
  5. Sci Adv. 2024 Feb 16. 10(7): eadk1721
    Mechanistic insight into glioma through spatially multidimensional proteomics.
    Lei Shen, Zhourui Zhang, Pengfei Wu, Jingyi Yang, Yuankun Cai, Keyu Chen, Songshan Chai, Jingwei Zhao, Hongyu Chen, Xuan Dai, Bangkun Yang, Wei Wei, Lixin Dong, Jincao Chen, Pucha Jiang, Changjun Cao, Chao Ma, Chengshi Xu, Yichun Zou, Jibo Zhang, Wenping Xiong, Zhengwei Li, Shuangxiang Xu, Bing Shu, Mengyang Wang, Zejin Li, Qiongqiong Wan, Nanxiang Xiong, Suming Chen.
      Characterizing the tumor microenvironment at the molecular level is essential for understanding the mechanisms of tumorigenesis and evolution. However, the specificity of the blood proteome in localized region of the tumor and its linkages with other systems is difficult to investigate. Here, we propose a spatially multidimensional comparative proteomics strategy using glioma as an example. The blood proteome signature of tumor microenvironment was specifically identified by in situ collection of arterial and venous blood from the glioma region of the brain for comparison with peripheral blood. Also, by integrating with different dimensions of tissue and peripheral blood proteomics, the information on the genesis, migration, and exchange of glioma-associated proteins was revealed, which provided a powerful method for tumor mechanism research and biomarker discovery. The study recruited multidimensional clinical cohorts, allowing the proteomic results to corroborate each other, reliably revealing biological processes specific to gliomas, and identifying highly accurate biomarkers.
    DOI:  https://doi.org/10.1126/sciadv.adk1721
  6. ACS Nano. 2024 Feb 13.
    Antigen Self-Presented Personalized Nanovaccines Boost the Immunotherapy of Highly Invasive and Metastatic Tumors.
    Tingting Wang, Mengxiao Han, Yaobao Han, Zhilin Jiang, Qing Zheng, Hao Zhang, Zhen Li.
      Dendritic cell (DC)-based vaccines have shown promise in adoptive cell therapy for enhancing the antigen-specific response of antitumor immunity. However, their clinical efficacy is limited by the less-presented tumor-associated antigens (TAAs) through MHC I and low lymph node homing efficiency. Herein, to address these issues, we rationally design and fabricate DC-based nanovaccines by coating Cu2-xSe nanoparticles (CS NPs) with the membrane of matured DCs (named as DCNV(CSD) nanovaccines). We reveal the important roles of CS NPs in the DCNV(CSD) nanovaccines from three aspects: (1) inducing the immunogenic cell death of tumor cells to expose abundant TAAs; (2) promoting the escape of TAAs from the lysosomes of DCs during the antigen presenting process through MHC I; (3) sustainably releasing traces of copper ions to promote the proliferation of T cells. Our DCNV(CSD) nanovaccines are characterized with high expressions of MHC I, CD80, CD86, CCR7, and ICAM-1 proteins, which not only endow them with abundantly processed specific TAAs, but also a strong capability of homing to the lymph nodes. The homing capability of our small DCNV(CSD) nanovaccines is better than that of matured DCs. More importantly, they can elicit the strong response of potent antispecific CD8+ T cells for antitumor immunotherapy, as tested in the treatment of highly invasive glioblastoma and highly metastatic melanoma. Additionally, DCNV(CSD) nanovaccines can generate memory T cells (TEM) in the spleen of mice to effectively prevent the recurrence of treated tumors. This work demonstrates a universal approach to fabricate high-performance DC-based nanovaccines for tumor immunotherapy by using versatile CS NPs.
    Keywords:  glioblastoma; immunotherapy; lymph nodes homing; lysosomal escape; personalized DC-based nanovaccines
    DOI:  https://doi.org/10.1021/acsnano.3c11189
  7. J Clin Invest. 2024 Feb 15. pii: e176613. [Epub ahead of print]134(4):
    Cancer-associated fibroblast-secreted collagen is associated with immune inhibitor receptor LAIR1 in gliomas.
    Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Jason Miska, Kathleen McCortney, Alicia Steffens, Jordain Walshon, Daniel Winkowski, Michael Cloney, Matthew Ordon, William Gibson, Hanna Kemeny, Mark Youngblood, Rebecca Du, James Mossner, Pavlos Texakalidis, Annelise Sprau, Matthew Tate, Charles David James, Craig M Horbinski, Nitin R Wadhwani, Maciej S Lesniak, Sandi Lam, Ankita Sati, Manish Aghi, Michael DeCuypere, Amy B Heimberger.
      
    Keywords:  Brain cancer; Cell Biology; Collagens; Macrophages; Oncology
    DOI:  https://doi.org/10.1172/JCI176613
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