Novel Experimental Therapeutic Targets and Strategies for Brain Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 11185

Special Issue Editors

Hugo W. Moser Research Institute at Kennedy Krieger and Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Interests: glioblastoma; brain tumors

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Guest Editor
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22903, USA
Interests: basic and translational brain tumor research

Special Issue Information

Dear Colleagues,

Brain cancers are one of the most deadly tumors with poor prognoses. The 5-year survival rate for people with a cancerous brain or CNS tumor in the USA is about 36%, despite the advances in surgical resection and ionizing radiation +/− chemotherapy. Since treating malignant brain tumors is frustratingly ineffective, it is imperative to identify novel therapeutic targets and approaches, and develop more effective combinational therapies.

This Special Issue focuses on the identification of new experimental therapeutic targets and/or the development of new therapeutic strategies for adult and pediatric brain tumors. We are particularly (but not exclusively) interested in drugs and approaches that sensitize tumors to standard-of-care radiotherapy, chemotherapy, and immunotherapy, as well as clinical trials with small molecule inhibitors and other drugs. We are also seeking articles that describe novel combinational therapies and innovative drug delivery approaches. We are pleased to invite you to submit original research articles and reviews on the above areas of research. We hope that this Special Issue will enhance our understanding of brain tumors and the development and testing of new therapies. We look forward to receiving your contributions.

Dr. Yunqing Li
Prof. Dr. Roger Abounader
Guest Editors

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Keywords

  • brain tumors
  • glioma
  • glioblastoma
  • medulloblastoma
  • radiotherapy
  • chemotherapy
  • immunotherapy
  • combination therapy
  • microRNAs
  • oncogene signaling pathways
  • epigenetic regulation
  • metabolic regulation
  • nanotechnology
  • drug delivery

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Published Papers (5 papers)

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Research

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17 pages, 3800 KiB  
Article
miR-217-5p NanomiRs Inhibit Glioblastoma Growth and Enhance Effects of Ionizing Radiation via EZH2 Inhibition and Epigenetic Reprogramming
by Jack Korleski, Sweta Sudhir, Yuan Rui, Christopher A. Caputo, Sophie Sall, Amanda L. Johnson, Harmon S. Khela, Tanmaya Madhvacharyula, Anisha Rasamsetty, Yunqing Li, Bachchu Lal, Weiqiang Zhou, Karen Smith-Connor, Stephany Y. Tzeng, Jordan J. Green, John Laterra and Hernando Lopez-Bertoni
Cancers 2025, 17(1), 80; https://doi.org/10.3390/cancers17010080 - 30 Dec 2024
Viewed by 1433
Abstract
Background/Objectives: CSCs are critical drivers of the tumor and stem cell phenotypes of glioblastoma (GBM) cells. Chromatin modifications play a fundamental role in driving a GBM CSC phenotype. The goal of this study is to further our understanding of how stem cell-driving [...] Read more.
Background/Objectives: CSCs are critical drivers of the tumor and stem cell phenotypes of glioblastoma (GBM) cells. Chromatin modifications play a fundamental role in driving a GBM CSC phenotype. The goal of this study is to further our understanding of how stem cell-driving events control changes in chromatin architecture that contribute to the tumor-propagating phenotype of GBM. Methods: We utilized computational analyses to identify a subset of clinically relevant genes that were predicted to be repressed in a Polycomb repressive complex 2 (PRC2)-dependent manner in GBM upon induction of stem cell-driving events. These associations were validated in patient-derived GBM neurosphere models using state-of-the-art molecular techniques to express, silence, and measure microRNA (miRNA) and gene expression changes. Advanced Poly(β-amino ester) nanoparticle formulations (PBAEs) were used to deliver miRNAs in vivo to orthotopic human GBM tumor models. Results: We show that glioma stem cell (GSC) formation and tumor propagation involve the crosstalk between multiple epigenetic mechanisms, resulting in the repression of the miRNAs that regulate PRC2 function and histone H3 lysine 27 tri-methylation (H3K27me3). We also identified miR-217-5p as an EZH2 regulator repressed in GSCs and showed that miR-217-5p reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed genes, inhibits GSC formation, impairs tumor growth, and enhances the effects of ionizing radiation in an orthotopic model of GBM. Conclusions: These findings suggest that inhibiting PRC2 function by targeting EZH2 with miR-217-5p advanced nanoparticle formulations could have a therapeutic benefit in GBM. Full article
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13 pages, 6624 KiB  
Article
Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma
by Amber B. Jones, Kaysaw Tuy, Cyntanna C. Hawkins, Colin H. Quinn, Joelle Saad, Sam E. Gary, Elizabeth A. Beierle, Lei Ding, Kate M. Rochlin, Lawrence S. Lamb and Anita B. Hjelmeland
Cancers 2024, 16(16), 2852; https://doi.org/10.3390/cancers16162852 - 15 Aug 2024
Cited by 3 | Viewed by 2019
Abstract
Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. [...] Read more.
Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. We sought to determine whether the addition of the blood–brain barrier penetrant PARP inhibitor niraparib to the standard of care DNA alkylator temozolomide (TMZ) could upregulate NKG2DL, thereby improving immune cell recognition. Changes in viability were consistent with prior publications as there was a growth inhibitory effect of the combination of TMZ and niraparib. However, decreases in viability did not always correlate with changes in NKG2DL mRNA. ULBP1/Mult-1 mRNA was increased with the combination therapy in comparison to either drug alone in two of the three cell types tested, even though viability was consistently decreased. mRNA expression correlated with protein levels and ULBP1/MULT-1 cell surface protein was significantly increased with TMZ and niraparib treatment in four of the five cell types tested. Gamma delta T cell-mediated cytotoxicity at a 10:1 effector-to-target ratio was significantly increased upon pretreatment of cells derived from a GBM PDX with TMZ and niraparib in comparison to the control or either drug alone. Together, these data demonstrate that the combination of PARP inhibition, DNA alkylation, and gamma delta T cell therapy has the potential for the treatment of GBM. Full article
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16 pages, 9024 KiB  
Article
Phase I/II Trial of Urokinase Plasminogen Activator-Targeted Oncolytic Newcastle Disease Virus for Canine Intracranial Tumors
by John H. Rossmeisl, Jamie N. King, John L. Robertson, James Weger-Lucarelli and Subbiah Elankumaran
Cancers 2024, 16(3), 564; https://doi.org/10.3390/cancers16030564 - 29 Jan 2024
Cited by 3 | Viewed by 2034
Abstract
Neurotropic oncolytic viruses are appealing agents to treat brain tumors as they penetrate the blood–brain barrier and induce preferential cytolysis of neoplastic cells. The pathobiological similarities between human and canine brain tumors make immunocompetent dogs with naturally occurring tumors attractive models for the [...] Read more.
Neurotropic oncolytic viruses are appealing agents to treat brain tumors as they penetrate the blood–brain barrier and induce preferential cytolysis of neoplastic cells. The pathobiological similarities between human and canine brain tumors make immunocompetent dogs with naturally occurring tumors attractive models for the study of oncolytic virotherapies. In this dose-escalation/expansion study, an engineered Lasota NDV strain targeting the urokinase plasminogen activator system (rLAS-uPA) was administered by repetitive intravenous infusions to 20 dogs with intracranial tumors with the objectives of characterizing toxicities, immunologic responses, and neuroradiological anti-tumor effects of the virus for up to 6 months following treatment. Dose-limiting toxicities manifested as fever, hematologic, and neurological adverse events, and the maximum tolerated dose (MTD) of rLAS-uPA was 2 × 107 pfu/mL. Mild adverse events, including transient infusion reactions, diarrhea, and fever were observed in 16/18 of dogs treated at or below MTD. No infectious virus was recoverable from body fluids. Neutralizing antibodies to rLAS-uPA were present in all dogs by 2 weeks post-treatment, and viral genetic material was detected in post-treatment tumors from six dogs. Tumor volumetric reductions occurred in 2/11 dogs receiving the MTD. Systemically administered rLAS-uPA NDV was safe and induced anti-tumor effects in canine brain tumors, although modifications to evade host anti-viral immunity are needed to optimize this novel therapy. Full article
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22 pages, 2384 KiB  
Article
Repurposing Clemastine to Target Glioblastoma Cell Stemness
by Michael A. Sun, Rui Yang, Heng Liu, Wenzhe Wang, Xiao Song, Bo Hu, Nathan Reynolds, Kristen Roso, Lee H. Chen, Paula K. Greer, Stephen T. Keir, Roger E. McLendon, Shi-Yuan Cheng, Darell D. Bigner, David M. Ashley, Christopher J. Pirozzi and Yiping He
Cancers 2023, 15(18), 4619; https://doi.org/10.3390/cancers15184619 - 18 Sep 2023
Cited by 2 | Viewed by 4077
Abstract
Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearing PDGFRA amplification. These [...] Read more.
Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearing PDGFRA amplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that the Emopamil Binding Protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is essential for BTIC propagation and a target that mediates the suppressive effects of clemastine. Finally, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment. Collectively, these results identify pathways essential for maintaining the stemness and progenitor features of GBMs, uncover BTIC dependency on EBP, and suggest that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment. Full article
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Review

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29 pages, 494 KiB  
Review
Exploring the Microbiome’s Impact on Glioma and Brain Metastases: Insights into Development, Progression, and Treatment Response—A Scoping Review
by Jennifer Leigh, Becky Skidmore, Adrian Wong, Saman Maleki Vareki and Terry L. Ng
Cancers 2025, 17(7), 1228; https://doi.org/10.3390/cancers17071228 - 4 Apr 2025
Viewed by 692
Abstract
Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut–brain axis. This [...] Read more.
Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut–brain axis. This scoping review synthesizes current evidence on the relationship between the human microbiome and brain tumors. Methods: A systematic search of five electronic databases was conducted by an expert librarian, using controlled vocabulary and keywords. A targeted grey literature search in Google Scholar and clinical trial registries was also undertaken. Eligible studies included primary research involving human patients, or in vivo, or in vitro models of glioma or brain metastasis, with a focus on the microbiome’s role in tumor development, treatment response, and outcomes. Results: Out of 584 citations screened, 40 studies met inclusion criteria, comprising 24 articles and 16 conference abstracts. These included 12 human studies, 16 using mouse models, 7 combining both, and 5 employing large datasets or next-generation sequencing of tumor samples. Thirty-one studies focused on primary brain tumors, six on brain metastases, and three on both. Of the 20 studies examining dysbiosis in tumor development, 95% (n = 19) found an association with tumor growth. Additionally, 71.4% (n = 5/7) of studies reported that microbiome alterations influenced treatment efficacy. Conclusions: Although the role of the gut–brain axis in brain tumors is still emerging and is characterized by heterogeneity across studies, existing evidence consistently supports a relationship between the gut microbiome and both brain tumor development and treatment outcomes. Full article
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