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Novel Insights into Glioblastoma and Brain Metastases

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

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 19796

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Prof. Dr. Sanjay K. Srivastava

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Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, TX 79601, USA
Interests: development of phytochemicals for cancer prevention and therapeutics; targeting STAT-3, NF-kB, HER2, MCL-1, AKT/FOXO, GLI1/2, and related signaling pathways with agents such as capsaicin, piperlongumine, penfluridol, isothiocyanates, diindolylmethane, panabinostat, cucurbitacin B, and deguelin in pancreatic, ovarian, breast, melanoma, and brain cancer; drug repurposing
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Dear Colleagues,

Glioblastoma is an aggressive grade IV brain tumor leading to severe fatalities globally. Moreover, several cancers lead to brain metastasis which is a major cause of mortality. Tackling these conditions has several challenges, with the most important being the blood–brain barrier (BBB) permeability. Significant research is required to overcome these challenges. With surgery and radiation therapy being the major treatment strategy for brain tumors, intensive research has also been conducted on chemotherapies. Targeted therapies are currently being developed with beneficial effects in cancers such as colorectal, breast, lung, and melanoma. Radiation therapy has also proven to be quite successful against brain metastasis. Thus, in this Special Issue, we invite you to contribute your work concerning glioblastoma, novel insights into its treatment and management, and different cancers leading to brain metastasis. This Special Issue aims to highlight all types of work, such as clinical, pre-clinical, translational, and basic research. We invite both original research articles and review articles in this Special Issue. This critical topic would appeal to a number of scientists and clinicians in the field. The articles may include (but are not limited to) treatment, management, diagnosis, clinical trials, and molecular insights for glioblastoma and brain metastasis caused by different cancers such as breast, melanoma, renal, lung, colorectal, etc.

Prof. Dr. Sanjay K. Srivastava
Guest Editor

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Keywords

glioblastoma
brain metastasis
surgery
radiation
chemotherapy
blood–brain barrier
immunotherapy
novel targets
oncogenes
tumor heterogeneity
drug discovery

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Published Papers (9 papers)

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Research

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11 pages, 1601 KiB

Open AccessArticle

Mitochondrial Iron Metabolism as a Potential Key Mediator of PD-L1 Thermal Regulation

by Gizzy Keeler, Stephenson B. Owusu, Mario Zanaty and Michael S. Petronek

Cancers 2024, 16(22), 3736; https://doi.org/10.3390/cancers16223736 - 5 Nov 2024

Viewed by 1058

Abstract

Glioblastoma (GBM) is the most common primary brain malignancy in the U.S. with a 5-year overall survival < 5% despite an aggressive standard of care. Laser interstitial thermal therapy (LITT) is a surgical approach to treating GBM that has gained traction, providing a safe option for reducing intracranial tumor burden. LITT is believed to potentially modulate GBM immune responses; however, the biochemical mechanisms underlying the modulation of immune checkpoints in GBM cells have been poorly characterized. The present study aimed to preliminarily evaluate the effects of thermal therapy and radiation on PD-L1 modulation in vitro, as a function of IDH mutational status. U87 cells and their IDH-mutant counterpart (U87^R132H), which was generated using a crispr-cas9 knock-in approach, were utilized for this preliminary evaluation. Cell heating was achieved by harvesting with trypsin centrifugation where the cell pellets were treated on a heat block for the associated time and temperature. Following thermal therapy, cells were resuspended and irradiated using a 37-Cesium irradiator at 0.6 Gy min⁻¹. Immediately following treatment, cells were either plated as single cells to allow colonies to form, and stained with Coomassie blue to be counted approximately 10–14 days later or harvested for Western blot analysis. Cell lysates were analyzed for PD-L1 expression with respect to various iron metabolic parameters (mortalin (HSPA9), transferrin receptor, and ferritin heavy chain) using a Western blotting approach. In both U87 and U87^R132H cell lines, thermal therapy showed a temperature-dependent cell-killing effect, but U87^R132H cells appeared more sensitive to thermal treatment when treated at 43 °C for 10 min. Moreover, thermal therapy had minimal effects on cell responses to 2 Gy irradiation. Treatment with thermal therapy downregulated PD-L1 expression in U87^R132H cells, which was associated with increased expression of the mitochondrial iron metabolic enzyme, HSPA9. Thermal therapy reversed the radiation-induced overexpression of PD-L1, transferrin receptor, and ferritin heavy chain in U87^R132H cells. No effects were observed in wild-type U87 cells. Moreover, Ga(NO₃)₃ depleted mitochondrial iron content which, in turn, significantly enhanced the sensitivity of U87^R132H cells to thermal therapy and 2 Gy irradiation and caused a significant increase in PD-L1 expression. These results suggest that thermal therapy alone can modulate the immune checkpoint PD-L1. This effect was more pronounced when thermal therapy was combined with radiation. Mechanistically, mitochondrial iron trafficking through HSPA9 may coordinate the regulation of PD-L1 in the context of thermal therapy and ionizing radiation, which can be targeted with gallium-based therapy. These novel, preliminary findings warrant further mechanistic investigations in pre-clinical models of LITT. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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14 pages, 2923 KiB

Open AccessArticle

Local Delivery of Irinotecan to Recurrent GBM Patients at Reoperation Offers a Safe Route of Administration

by Christopher McConville, Sarah Lastakchi, Ali Al Amri, Desire Ngoga, Oluwafikayo Fayeye and Garth Cruickshank

Cancers 2024, 16(17), 3008; https://doi.org/10.3390/cancers16173008 - 29 Aug 2024

Viewed by 1312

Abstract

Glioblastomas are impossible to completely resect and almost always recur at the borders of the resection margin. There is no established chemotherapy regimen available to patients who recur, while systemic treatment is hampered by the blood–brain barrier. Here, we report on the first evaluation in humans of the intraparenchymal injection of irinotecan into the resection cavity after surgical resection of recurrent glioblastoma patients. The cytotoxicity of irinotecan was compared to SN-38 in primary cells from recurrent glioblastoma patients. Irinotecan was injected at multiple (~30) sites of the resection cavity wall at a depth of 3 to 5 mm. SN-38 was more cytotoxic than irinotecan at concentrations below 1 µM due to enzyme kinetics. The intraparenchymal administration of irinotecan was safe, with good wound healing and an absence of swelling, inflammation, or pseudo-abscess formation. The median survival post irinotecan administration was 32.6 weeks. The median overall survival was 30.5 months, with a two-year survival rate of 56%. This study demonstrates that local delivery of irinotecan into the brain parenchyma offers a safe route of administration over systemic delivery in the treatment of recurrent glioblastoma. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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19 pages, 4390 KiB

Open AccessArticle

Proline Metabolism in WHO G4 Gliomas Is Altered as Compared to Unaffected Brain Tissue

by Magdalena M. Sawicka, Karol Sawicki, Marek Jadeszko, Katarzyna Bielawska, Elżbieta Supruniuk, Joanna Reszeć, Izabela Prokop-Bielenia, Barbara Polityńska, Mateusz Jadeszko, Magdalena Rybaczek, Eryk Latoch, Krzysztof Gorbacz, Tomasz Łysoń and Wojciech Miltyk

Cancers 2024, 16(2), 456; https://doi.org/10.3390/cancers16020456 - 21 Jan 2024

Cited by 1 | Viewed by 1968

Abstract

Proline metabolism has been identified as a significant player in several neoplasms, but knowledge of its role in gliomas is limited despite it providing a promising line of pursuit. Data on proline metabolism in the brain are somewhat historical. This study aims to investigate alterations of proline metabolism in gliomas of WHO grade 4 (GG4) in the context of the brain. A total of 20 pairs of samples were studied, consisting of excised tumor and unaffected brain tissue, obtained when partial brain resection was required to reach deep-seated lesions. Levels of proline oxidase/proline dehydrogenase (POX/PRODH), Δ¹-pyrroline-5-carboxylate reductases (PYCR1/2/3), prolidase (PEPD), and metalloproteinases (MMP-2, MMP-9) were assessed, along with the concentration of proline and proline-related metabolites. In comparison to normal brain tissue, POX/PRODH expression in GG4 was found to be suppressed, while PYCR1 expression and activity of PEPD, MMP-2, and -9 were upregulated. The GG4 proline concentration was 358% higher. Hence, rewiring of the proline metabolism in GG4 was confirmed for the first time, with a low-POX/PRODH/high-PYCR profile. High PEPD and MMPs activity is in keeping with GG4-increased collagen turnover and local aggressiveness. Further studies on the mechanisms of the interplay between altered proline metabolism and the GG4 microenvironment are warranted. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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11 pages, 1533 KiB

Open AccessArticle

Intramedullary Spinal Cord Tumors: Whole-Genome Sequencing to Assist Management and Prognosis

by Miguel Mayol del Valle, Bryan Morales, Brandon Philbrick, Segun Adeagbo, Subir Goyal, Sarah Newman, Natasha L. Frontera, Edjah Nduom, Jeffrey Olson, Stewart Neill and Kimberly Hoang

Cancers 2024, 16(2), 404; https://doi.org/10.3390/cancers16020404 - 18 Jan 2024

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Abstract

Intramedullary spinal cord tumors (IMSCTs) harbor unique genetic mutations which may play a role in prognostication and management. To this end, we present the largest cohort of IMSCTs with genetic characterization in the literature from our multi-site institutional registry. A total of 93 IMSCT patient records were reviewed from the years 1999 to 2020. Out of these, 61 complied with all inclusion criteria, 14 of these patients had undergone genetic studies with 8 undergoing whole-genomic sequencing. Univariate analyses were used to assess any factors associated with progression-free survival (PFS) using the Cox proportional hazards model. Firth’s penalized likelihood approach was used to account for the low event rates. Fisher’s exact test was performed to compare whole-genome analyses and specific gene mutations with progression. PFS (months) was given as a hazard ratio. Only the absence of copy neutral loss of heterozygosity (LOH) was shown to be significant (0.05, p = 0.008). Additionally, higher risk of recurrence/progression was associated with LOH (p = 0.0179). Our results suggest LOH as a genetic predictor of shorter progression-free survival, particularly within ependymoma and glioblastoma tumor types. Further genomic research with larger multi-institutional datasets should focus on these mutations as possible prognostic factors. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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16 pages, 2454 KiB

Open AccessArticle

In Vitro and In Vivo Drug-Response Profiling Using Patient-Derived High-Grade Glioma

by Robin G. Rajan, Virneliz Fernandez-Vega, Jantzen Sperry, Jonathan Nakashima, Long H. Do, Warren Andrews, Simina Boca, Rezwanul Islam, Sajeel A. Chowdhary, Jan Seldin, Glauco R. Souza, Louis Scampavia, Khalid A. Hanafy, Frank D. Vrionis and Timothy P. Spicer

Cancers 2023, 15(13), 3289; https://doi.org/10.3390/cancers15133289 - 22 Jun 2023

Cited by 5 | Viewed by 3170

Abstract

Background: Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach. Methods: High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma. RNAseq analysis supplemented this 128-compound screening to predict more efficacious and patient-specific drug combinations with additional tumor stemness evaluated using flow cytometry. In vivo PDX mouse models rapidly validated (50 days) and determined mutational influence alongside of drug efficacy. We present a representative GBM case of three tumors resected at initial presentation, at first recurrence without any treatment, and at a second recurrence following radiation and chemotherapy, all from the same patient. Results: Molecular and in vitro screening helped identify effective drug targets against several pathways as well as synergistic drug combinations of cobimetinib and vemurafenib for this patient, supported in part by in vivo tumor growth assessment. Each tumor iteration showed significantly varying stemness and drug resistance. Conclusions: Our integrative model utilizing molecular, in vitro, and in vivo approaches provides direct evidence of a patient’s tumor response drifting with treatment and time, as demonstrated by dynamic changes in their tumor profile, which may affect how one would address that drift pharmacologically. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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12 pages, 847 KiB

Open AccessArticle

Preoperative Prognostic Index for Patients with Brain Metastases—A Population-Based Multi-Centre Study

by Rebecca Rootwelt Winther, Eva Skovlund, Joakim Stray Andreassen, Lisa Arvidsson, Jonathan Halvardson, Ole Solheim, Jiri Bartek, Stein Kaasa, Marianne Jensen Hjermstad and Einar Osland Vik-Mo

Cancers 2023, 15(12), 3174; https://doi.org/10.3390/cancers15123174 - 13 Jun 2023

Viewed by 1561

Abstract

Background: Brain metastases (BM) are common in cancer patients and are associated with high morbidity and mortality. Surgery is an option, but the optimal selection of patients for surgery is challenging and controversial. Current prognostication tools are not ideal for preoperative prognostication. By using a reference population (derivation data set) and two external populations (validation data set) of patients who underwent surgery for BM, we aimed to create and validate a preoperative prognostic index. Methods: The derivation data set consists of 590 patients who underwent surgery for BM (2011–2018) at Oslo University Hospital. We identified variables associated with survival and created a preoperative prognostic index with four prognostic groups, which was validated on patients who underwent surgery for BM at Karolinska University Hospital and St. Olavs University Hospital during the same time period. To reduce over-fitting, we adjusted the index in accordance with our findings. Results: 438 patients were included in the validation data set. The preoperative prognostic index correctly divided patients into four true prognostic groups. The two prognostic groups with the poorest survival outcomes overlapped, and these were merged to create the adjusted preoperative prognostic index. Conclusion: We created a prognostic index for patients with BM that predicts overall survival preoperatively. This index might be valuable in supporting informed choice when considering surgery for BM. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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19 pages, 4229 KiB

Open AccessArticle

Neuronal Cannabinoid CB₁ Receptors Suppress the Growth of Melanoma Brain Metastases by Inhibiting Glutamatergic Signalling

by Carlos Costas-Insua, Marta Seijo-Vila, Cristina Blázquez, Sandra Blasco-Benito, Francisco Javier Rodríguez-Baena, Giovanni Marsicano, Eduardo Pérez-Gómez, Cristina Sánchez, Berta Sánchez-Laorden and Manuel Guzmán

Cancers 2023, 15(9), 2439; https://doi.org/10.3390/cancers15092439 - 24 Apr 2023

Cited by 3 | Viewed by 4368

Abstract

Melanoma is one of the deadliest forms of cancer. Most melanoma deaths are caused by distant metastases in several organs, especially the brain, the so-called melanoma brain metastases (MBMs). However, the precise mechanisms that sustain the growth of MBMs remain elusive. Recently, the excitatory neurotransmitter glutamate has been proposed as a brain-specific, pro-tumorigenic signal for various types of cancers, but how neuronal glutamate shuttling onto metastases is regulated remains unknown. Here, we show that the cannabinoid CB₁ receptor (CB₁R), a master regulator of glutamate output from nerve terminals, controls MBM proliferation. First, in silico transcriptomic analysis of cancer-genome atlases indicated an aberrant expression of glutamate receptors in human metastatic melanoma samples. Second, in vitro experiments conducted on three different melanoma cell lines showed that the selective blockade of glutamatergic NMDA receptors, but not AMPA or metabotropic receptors, reduces cell proliferation. Third, in vivo grafting of melanoma cells in the brain of mice selectively devoid of CB₁Rs in glutamatergic neurons increased tumour cell proliferation in concert with NMDA receptor activation, whereas melanoma cell growth in other tissue locations was not affected. Taken together, our findings demonstrate an unprecedented regulatory role of neuronal CB₁Rs in the MBM tumour microenvironment. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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Review

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17 pages, 4428 KiB

Open AccessReview

m⁶A mRNA Modifications in Glioblastoma: Emerging Prognostic Biomarkers and Therapeutic Targets

by Gloria S. Xie and Hope T. Richard

Cancers 2024, 16(4), 727; https://doi.org/10.3390/cancers16040727 - 9 Feb 2024

Cited by 2 | Viewed by 2512

Abstract

Glioblastoma, the most common and aggressive primary brain tumor, is highly invasive and neurologically destructive. The mean survival for glioblastoma patients is approximately 15 months and there is no effective therapy to significantly increase survival times to date. The development of effective therapy including mechanism-based therapies is urgently needed. At a molecular biology level, N6-methyladenine (m⁶A) mRNA modification is the most abundant posttranscriptional RNA modification in mammals. Recent studies have shown that m⁶A mRNA modifications affect cell survival, cell proliferation, invasion, and immune evasion of glioblastoma. In addition, m⁶A mRNA modifications are critical for glioblastoma stem cells, which could initiate the tumor and lead to therapy resistance. These findings implicate the function of m⁶A mRNA modification in tumorigenesis and progression, implicating its value in prognosis and therapies of human glioblastoma. This review focuses on the potential clinical significance of m⁶A mRNA modifications in prognostic and therapeutics of glioblastoma. With the identification of small-molecule compounds that activate or inhibit components of m⁶A mRNA modifications, a promising novel approach for glioblastoma therapy is emerging. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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27 pages, 1021 KiB

Open AccessSystematic Review

Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment: A Systematic Review

by Archit Bharathwaj Baskaran, Olivia A. Kozel, Omkar Venkatesh, Derek A. Wainwright, Adam M. Sonabend, Amy B. Heimberger and Rimas Vincas Lukas

Cancers 2024, 16(24), 4148; https://doi.org/10.3390/cancers16244148 - 12 Dec 2024

Viewed by 1024

Abstract

Purpose: A glioblastoma (GBM) is a primary brain tumor with significant unmet therapeutic needs. Immune checkpoint inhibitors (ICIs) have marked therapeutic benefits in many different cancers but have yet to show benefit for most GBM patients in phase III trials. Methods: A systematic review querying ClinicalTrials.gov for prospective clinical trials investigating ICI in GBM between 1950 and July 2024 was performed. Search terms comprised 11 distinct ICIs. Data abstracted include clinical trial NCT numbers with study titles and status, enrollment information, interventions, and more. Clinical trial identifying information, interventions, and outcomes were extracted. Results: One hundred and seventeen clinical trials were identified; four were phase 3. Most involved PD-1 or CTLA-4 blockade as monotherapy or in combination with standard-of-care. The large, randomized trials included CHECKMATE 143, CHECKMATE 498, CHECKMATE 548, and NRG BN007. These showed no improvement in median overall survival or progression-free survival in unselected patients. Biomarker-directed analyses suggest that a subset of GBM patients may benefit. Conclusions: ICI for the treatment of GBM has not demonstrated clear evidence of efficacy thus far. This review serves as a quick reference of ICI trial results in GBM. Biomarker-driven patient selection and/or novel approaches to overcome resistance mechanisms remain areas of viable inquiry. Full article

(This article belongs to the Special Issue Novel Insights into Glioblastoma and Brain Metastases)

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