Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Hersh, Andrew; Gaitsch, Hallie; Alomari, Safwan; Lubelski, Daniel; Tyler, Betty

doi:10.3390/cancers14153743

Cited by 25 publications

(20 citation statements)

References 294 publications

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“…The glioblastoma cell population is heterogeneous, with tumor-differentiated cells coexisting with subpopulations displaying stem cell characteristics. It is thought that GSCs derived from the normal NS/PC compartment [ 27 ] are responsible for recurrence and clinical relapse of glioblastoma [ 28 , 29 , 30 ]. Given that pharmacological modulation of the TRP ion channel activity in cancer cells is linked to their sensitivity to chemotherapeutic drugs [ 31 ], our goal was to examine the TRPML2 expression in GSCs and its relationship to resistance to TMZ, the standard chemotherapy for newly diagnosed GBM since 2005 and the subsequent use of the Stupp regimen [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

Morelli

Nabissi

Amantini

et al. 2022

IJMS

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The survival of patients with glioblastoma (GBM) is poor. The main cause is the presence of glioma stem cells (GSCs), exceptionally resistant to temozolomide (TMZ) treatment. This last may be related to the heterogeneous expression of ion channels, among them TRPML2. Its mRNA expression was evaluated in two different neural stem cell (NS/PC) lines and sixteen GBM stem-like cells by qRT-PCR. The response to TMZ was evaluated in undifferentiated or differentiated GSCs, and in TRPML2-induced or silenced GSCs. The relationship between TRPML2 expression and responsiveness to TMZ treatment was evaluated by MTT assay showing that increased TRPML2 mRNA levels are associated with resistance to TMZ. This research was deepened by qRT-PCR and western blot analysis. PI3K/AKT and JAK/STAT pathways as well as ABC and SLC drug transporters were involved. Finally, the relationship between TRPML2 expression and overall survival (OS) and progression-free survival (PFS) in patient-derived GSCs was evaluated by Kaplan–Meier analysis. The expression of TRPML2 mRNA correlates with worse OS and PFS in GBM patients. Thus, the expression of TRPML2 in GSCs influences the responsiveness to TMZ in vitro and affects OS and PFS in GBM patients.

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Section: Discussionmentioning

confidence: 99%

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

Morelli

Nabissi

Amantini

et al. 2022

IJMS

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“…Epidermal growth factor receptor (EGFR) is overexpressed in 60% of primary GBMs ( Hersh et al., 2022 ). KNE ( Table 2 ) was retargeted to human EGFR- and EGFRvIII-overexpressing cells by inserting an scFv against EGFR into gD, which was also mutated for the HVEM and nectin-1 binding sites, and with gB mutations that enhance entry ( Uchida et al., 2013 ).…”

Section: Making Hsv Oncolytic and Safe In The Brainmentioning

confidence: 99%

“…Epigenetic alterations regulate expression of GSC stemness and DDR ( Hersh et al., 2022 ). oHSV infection induces innate immunity, which inhibits virus replication and spread, while histone deacetylase (HDAC) inhibitors can upregulate virus gene expression and downregulate IFN-stimulated genes ( Nakashima et al., 2015b ).…”

Section: Combination Therapy With Drugsmentioning

confidence: 99%

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Oncolytic herpes simplex viruses for the treatment of glioma and targeting glioblastoma stem-like cells

Kardani

Gil

Rabkin

2023

Front. Cell. Infect. Microbiol.

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Glioblastoma (GBM) is one of the most lethal cancers, having a poor prognosis and a median survival of only about 15 months with standard treatment (surgery, radiation, and chemotherapy), which has not been significantly extended in decades. GBM demonstrates remarkable cellular heterogeneity, with glioblastoma stem-like cells (GSCs) at the apex. GSCs are a subpopulation of GBM cells that possess the ability to self-renew, differentiate, initiate tumor formation, and manipulate the tumor microenvironment (TME). GSCs are no longer considered a static population of cells with specific markers but are quite flexible phenotypically and in driving tumor heterogeneity and therapeutic resistance. In light of these features, they are a critical target for successful GBM therapy. Oncolytic viruses, in particular oncolytic herpes simplex viruses (oHSVs), have many attributes for therapy and are promising agents to target GSCs. oHSVs are genetically-engineered to selectively replicate in and kill cancer cells, including GSCs, but not normal cells. Moreover, oHSV can induce anti-tumor immune responses and synergize with other therapies, such as chemotherapy, DNA repair inhibitors, and immune checkpoint inhibitors, to potentiate treatment effects and reduce GSC populations that are partly responsible for chemo- and radio-resistance. Herein, we present an overview of GSCs, activity of different oHSVs, clinical trial results, and combination strategies to enhance efficacy, including therapeutic arming of oHSV. Throughout, the therapeutic focus will be on GSCs and studies specifically targeting these cells. Recent clinical trials and approval of oHSV G47Δ in Japan for patients with recurrent glioma demonstrate the efficacy and promise of oHSV therapy.

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“…Liquid biopsies could be used for more frequent follow-up compared to MRI scans. Additionally, the molecular profile of tumor cells and tumor stem-like cells driving proliferative activity can be analyzed to generate personalized therapies [80]. Several clinical trials are underway examining use of liquid biopsies in intracranial tumors [81].…”

Section: Spine Incidental Intraduralmentioning

confidence: 99%

Approaches to Incidental Intradural Tumors of the Spine in the Pediatric Population

Hersh¹,

Lubelski²,

Theodore³

et al. 2023

Pediatr Neurosurg

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Background: Incidental intradural tumors of the spine in the pediatric population are rare lesions whose management remains unclear. Surgeons must balance the risks of iatrogenic deficits and complications after surgical resection against the risks from progressive growth of the tumor. Moreover, the natural history of an incidental finding can be difficult to predict. Here we review the literature on incidental intradural tumors of the spine and present considerations for their management. Summary: Growth of the tumor or changes in radiographic features are usually indications for resection. Asymptomatic lesions can be found in patients with genetic syndromes that predispose to tumor formation, such as neurofibromatosis type 1 and 2, schwannomatosis, and Von-Hippel-Lindau syndrome, and careful workup of a genetic cause is warranted in any patient presenting with multiple tumors and/or cutaneous features. Close follow-up is generally favored given the heavy tumor burden; however, some recommend pre-emptive resection to prevent permanent neurological deficits. Incidental intradural tumors can also occur in association with hydrocephalus, significant syringomyelia, and cord compression, and surgical treatment is usually warranted. Tumors may also be discovered as part of the workup for scoliosis, where they are not truly incidental to the scoliosis but rather are contributing to curve deformation. Key Messages: Thorough workup of patients for associated genetic syndromes or comorbidities should be undertaken in pediatric patients with incidental intradural tumors. Further research is needed into the natural history of these incidental lesions. Incidental tumors can often be managed conservatively with close follow-up, with surgical intervention warranted for expanding tumors or new-onset symptoms.

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Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Cited by 25 publications

References 294 publications

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

Oncolytic herpes simplex viruses for the treatment of glioma and targeting glioblastoma stem-like cells

Approaches to Incidental Intradural Tumors of the Spine in the Pediatric Population

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