Glioblastoma targeted therapy

Glioblastoma targeted therapy


Glioblastoma chemotherapy is limited due to the blood-brain barrier (BBB), poor drug targeting, and short biological half-lives.


Resistance of high-grade tumors to treatment involves cancer stem cell features, deregulated cell division, acceleration of genomic errors, and the emergence of cellular variants that rely upon diverse signaling pathways. This heterogeneous tumor landscape limits the utility of the focal sampling provided by invasive biopsy when designing strategies for targeted therapy.


Yao et al. synthesized and characterized a biomimetic nano drug CMS/PEG-DOX-M. The CMS/PEG-DOX-M effectively and rapidly released DOX in U87 MG cells. Cell proliferation and apoptosis assays were examined by the MTT and TUNEL assays. The penetration of nano drugs through the BBB and anti-tumor efficacy were investigated in the orthotopic glioblastoma xenograft models.

They showed that CMS/PEG-DOX-M inhibited cell proliferation of U87 MG cells and effectively induced cell apoptosis of U87 MG cells. Intracranial antitumor experiments showed that free DOX hardly penetrated the BBB, but CMS/PEG-DOX-M effectively reached the orthotopic intracranial tumor through the BBB and significantly inhibited tumor growth. Immunofluorescence staining of orthotopic tumor tissue sections confirmed that nano drugs promoted apoptosis of tumor cells. This study developed a multimodal nano drug treatment system with the enhanced abilities of tumor-targeting, BBB penetration, and cancer-specific accumulation of chemotherapeutic drugs by combining chemotherapy and photothermal therapy. It can be used as a flexible and effective GBM treatment system and it may also be used for the treatment of other central nervous systems (CNS) tumors and extracranial tumors 1).


In a roadmap review paper, Parker et al. proposed and developed methods for enabling the mapping of cellular and molecular features in vivo to inform and optimize cancer treatment strategies in the brain. This approach leverages 1) the spatial and temporal advantages of in vivo imaging compared with surgical biopsy, 2) the rapid expansion of meaningful anatomical and functional MR signals, 3) widespread access to cellular and molecular information enabled by next-generation sequencing, and 4) the enhanced accuracy and computational efficiency of deep learning techniques. As multiple cellular variants may be present within volumes below the resolution of imaging, we describe a mapping process to decode micro- and even nano-scale properties from the macro-scale data by simultaneously utilizing complimentary multiparametric image signals acquired in routine clinical practice. We outline design protocols for future research efforts that marry revolutionary bio-information technologies, growing access to increased computational capability, and powerful statistical classification techniques to guide rational treatment selection 2)


Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failed due to complex regulatory networks. There is an ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor-associated macrophagedendritic cell vaccineCAR-T cell Therapytumor microenvironment, and a combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options 3).


Comprehensive approaches are necessary to gain maximally from promising targeted therapies. Common methods used for critical evaluation of targeted therapies for glioblastoma include (1) novel methods for targeted delivery for glioblastoma chemotherapy; (2) strategies for delivery through BBB and blood-tumor barriers; (3) innovations in radiotherapy for selective destruction of tumor; (4) techniques for local destruction of tumor; (5) tumor growth inhibitors; (6) immunotherapy; and (7) cell/gene therapies. Suggestions for improvements in glioblastoma therapy include: (1) controlled targeted delivery of anticancer therapy to glioblastoma through the BBB using nanoparticles and monoclonal antibodies; (2) direct introduction of genetically modified bacteria that selectively destroy cancer cells but spare the normal brain into the remaining tumor after resection; (3) use of better animal models for preclinical testing; and (4) personalized/precision medicine approaches to therapy in clinical trials and translation into practice of neurosurgery and neurooncology. Advances in these techniques suggest optimism for the future management of glioblastoma 4)


Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy defines the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of the disease. Specifically, targeting cell signalings frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tyrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma 5).


1)

Yao Z, Jiang X, Yao H, Wu Y, Zhang F, Wang C, Qi C, Zhao C, Wu Z, Qi M, Zhang J, Cao X, Wang Z, Wu F, Yao C, Liu S, Ling S, Xia H. Efficiently targeted therapy of glioblastoma xenograft via multifunctional biomimetic nanodrugs. Biomater Res. 2022 Dec 2;26(1):71. doi: 10.1186/s40824-022-00309-y. PMID: 36461108.
2)

Parker JG, Servati M, Diller EE, Cao S, Ho C, Lober R, Cohen-Gadol A. Targeting intra-tumoral heterogeneity of human brain tumors with in vivo imaging: A roadmap for imaging genomics from multiparametric MR signals. Med Phys. 2022 Nov 13. doi: 10.1002/mp.16059. Epub ahead of print. PMID: 36371678.
3)

Yang K, Wu Z, Zhang H, Zhang N, Wu W, Wang Z, Dai Z, Zhang X, Zhang L, Peng Y, Ye W, Zeng W, Liu Z, Cheng Q. Glioma targeted therapy: insight into future of molecular approaches. Mol Cancer. 2022 Feb 8;21(1):39. doi: 10.1186/s12943-022-01513-z. PMID: 35135556; PMCID: PMC8822752.
4)

Jain KK. A Critical Overview of Targeted Therapies for Glioblastoma. Front Oncol. 2018 Oct 15;8:419. doi: 10.3389/fonc.2018.00419. PMID: 30374421; PMCID: PMC6196260.
5)

Le Rhun E, Preusser M, Roth P, Reardon DA, van den Bent M, Wen P, Reifenberger G, Weller M. Molecular targeted therapy of glioblastoma. Cancer Treat Rev. 2019 Sep 11;80:101896. doi: 10.1016/j.ctrv.2019.101896. [Epub ahead of print] Review. PubMed PMID: 31541850.

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