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Open AccessEditorial

Potential Molecular Targets in the Treatment of Patients with CNS Tumors

by Edward Pan

Cancers 2023, 15(15), 3807; https://doi.org/10.3390/cancers15153807 - 27 Jul 2023

Cited by 1 | Viewed by 939

Abstract

The challenges in identifying effective therapies for CNS tumors continue to be daunting [...] Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

Research

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13 pages, 4150 KiB

Open AccessArticle

Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11

by Miranda M. Tallman, Abigail A. Zalenski, Ian Stabl, Morgan S. Schrock, Luke Kollin, Eliane de Jong, Kuntal De, Treg M. Grubb, Matthew K. Summers and Monica Venere

Cancers 2023, 15(12), 3173; https://doi.org/10.3390/cancers15123173 - 13 Jun 2023

Cited by 2 | Viewed by 1910

Abstract

Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement [...] Read more.

Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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11 pages, 437 KiB

Open AccessArticle

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010–2019 Retrospective Cohort Study

by Vineeth Tatineni, Patrick J. O’Shea, Shreya Saxena, Atulya A. Khosla, Ahmad Ozair, Rupesh R. Kotecha, Xuefei Jia, Yasmeen Rauf, Erin S. Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom and Manmeet S. Ahluwalia

Cancers 2023, 15(11), 3015; https://doi.org/10.3390/cancers15113015 - 1 Jun 2023

Cited by 3 | Viewed by 2320

Abstract

Introduction: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown [...] Read more.

Introduction: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. Methods: A retrospective review of NSCLCBM patients diagnosed during 2010–2019 at a tertiary-care US center was performed and reported following the ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. Results: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17–0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). Conclusions: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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14 pages, 1030 KiB

Open AccessArticle

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases

by Vineeth Tatineni, Patrick J. O’Shea, Ahmad Ozair, Atulya A. Khosla, Shreya Saxena, Yasmeen Rauf, Xuefei Jia, Erin S. Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom and Manmeet S. Ahluwalia

Cancers 2023, 15(8), 2382; https://doi.org/10.3390/cancers15082382 - 20 Apr 2023

Cited by 6 | Viewed by 2620

Abstract

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have [...] Read more.

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010–2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd–5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd–5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd–5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd–5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63–2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55–4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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18 pages, 3523 KiB

Open AccessArticle

GBM Cells Exhibit Susceptibility to Metformin Treatment According to TLR4 Pathway Activation and Metabolic and Antioxidant Status

by Isabele Fattori Moretti, Antonio Marcondes Lerario, Paula Rodrigues Sola, Janaína Macedo-da-Silva, Mauricio da Silva Baptista, Giuseppe Palmisano, Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie

Cancers 2023, 15(3), 587; https://doi.org/10.3390/cancers15030587 - 18 Jan 2023

Cited by 5 | Viewed by 2700

Abstract

Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We [...] Read more.

Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET + TMZ and MET + LPS + TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET + LPS + TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of SOD2 and genes related to the TLR4 signaling pathway, including IL1B and CXCL8. A172 cells attained upregulated antioxidant gene expression, particularly SOD1, TXN and PRDX1-5, while MET treatment led to cell-cycle arrest. In silico analysis of the TCGA-GBM-RNASeq dataset indicated that the glycolytic plurimetabolic (GPM)-GBM subtype had a transcriptomic profile which overlapped with U87MG cells, suggesting GBM cases exhibiting this metabolic background with an activated inflammatory TLR4 pathway may respond to MET treatment. For cases with upregulated CXCL8, coding for IL8 (a pro-angiogenic factor), combination treatment with an IL8 inhibitor may improve tumor growth control. The A172 cell line corresponded to the mitochondrial (MTC)-GBM subtype, where MET plus an antioxidant inhibitor, such as anti-SOD1, may be indicated as a combinatory therapy. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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18 pages, 3054 KiB

Open AccessArticle

Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study

by Motoo Nagane, Koichi Ichimura, Ritsuko Onuki, Daichi Narushima, Mai Honda-Kitahara, Kaishi Satomi, Arata Tomiyama, Yasuhito Arai, Tatsuhiro Shibata, Yoshitaka Narita, Takeo Uzuka, Hideo Nakamura, Mitsutoshi Nakada, Yoshiki Arakawa, Takanori Ohnishi, Akitake Mukasa, Shota Tanaka, Toshihiko Wakabayashi, Tomokazu Aoki, Shigeki Aoki, Soichiro Shibui, Masao Matsutani, Keisuke Ishizawa, Hideaki Yokoo, Hiroyoshi Suzuki, Satoshi Morita, Mamoru Kato and Ryo Nishikawa Show full author list Hide full author list

Cancers 2022, 14(22), 5522; https://doi.org/10.3390/cancers14225522 - 10 Nov 2022

Cited by 5 | Viewed by 2749

Abstract

We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, [...] Read more.

We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O⁶-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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25 pages, 23552 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways

by Khoa Pham, Allison R. Hanaford, Brad A. Poore, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart and Eric H. Raabe

Cancers 2022, 14(5), 1311; https://doi.org/10.3390/cancers14051311 - 3 Mar 2022

Cited by 12 | Viewed by 4723

Abstract

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis [...] Read more.

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions—in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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16 pages, 2166 KiB

Open AccessArticle

Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas

by Guangyang Yu, Ying Pang, Mythili Merchant, Chimene Kesserwan, Vineela Gangalapudi, Abdalla Abdelmaksoud, Alice Ranjan, Olga Kim, Jun S. Wei, Hsien-Chao Chou, Xinyu Wen, Sivasish Sindiri, Young K. Song, Liqiang Xi, Rosandra N. Kaplan, Terri S. Armstrong, Mark R. Gilbert, Kenneth Aldape, Javed Khan and Jing Wu

Cancers 2021, 13(23), 6092; https://doi.org/10.3390/cancers13236092 - 3 Dec 2021

Cited by 18 | Viewed by 3005

Abstract

Background: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Methods: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and [...] Read more.

Background: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Methods: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). Results: Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = −0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. Conclusion: TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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17 pages, 2274 KiB

Open AccessArticle

Multi-Platform Classification of IDH-Wild-Type Glioblastoma Based on ERK/MAPK Pathway: Diagnostic, Prognostic and Therapeutic Implications

by Maria-Magdalena Georgescu

Cancers 2021, 13(18), 4532; https://doi.org/10.3390/cancers13184532 - 9 Sep 2021

Cited by 10 | Viewed by 3901

Abstract

Glioblastoma is the most aggressive and frequent glioma in the adult population. Because current therapy regimens confer only minimal survival benefit, molecular subgrouping to stratify patient prognosis and therapy design is warranted. This study presents a multi-platform classification of glioblastoma by analyzing a [...] Read more.

Glioblastoma is the most aggressive and frequent glioma in the adult population. Because current therapy regimens confer only minimal survival benefit, molecular subgrouping to stratify patient prognosis and therapy design is warranted. This study presents a multi-platform classification of glioblastoma by analyzing a large, ethnicity-inclusive 101-adult-patient cohort. It defines seven non-redundant IDH-wild-type glioblastoma molecular subgroups, G1–G7, corresponding to the upstream receptor tyrosine kinase (RTK) and RAS-RAF segment of the ERK/MAPK signal transduction pathway. These glioblastoma molecular subgroups are classified as G1/EGFR, G2/FGFR3, G3/NF1, G4/RAF, G5/PDGFRA, G6/Multi-RTK, and G7/Other. The comprehensive genomic analysis was refined by expression landscaping of all RTK genes, as well as of the major associated growth pathway mediators, and used to hierarchically cluster the subgroups. Parallel demographic, clinical, and histologic pattern analyses were merged with the molecular subgrouping to yield the first inclusive multi-platform classification for IDH-wild-type glioblastoma. This straightforward classification with diagnostic and prognostic significance may be readily used in neuro-oncological practice and lays the foundation for personalized targeted therapy approaches. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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Review

Jump to: Editorial, Research

22 pages, 2755 KiB

Open AccessReview

DNA Methylation and Histone Modification in Low-Grade Gliomas: Current Understanding and Potential Clinical Targets

by Ahmad Ozair, Vivek Bhat, Reid S. Alisch, Atulya A. Khosla, Rupesh R. Kotecha, Yazmin Odia, Michael W. McDermott and Manmeet S. Ahluwalia

Cancers 2023, 15(4), 1342; https://doi.org/10.3390/cancers15041342 - 20 Feb 2023

Cited by 18 | Viewed by 4200

Abstract

Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I–IV (now 1–4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors [...] Read more.

Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I–IV (now 1–4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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13 pages, 302 KiB

Open AccessReview

Preclinical Models of Low-Grade Gliomas

by Pushan Dasgupta, Veerakumar Balasubramanyian, John F. de Groot and Nazanin K. Majd

Cancers 2023, 15(3), 596; https://doi.org/10.3390/cancers15030596 - 18 Jan 2023

Cited by 8 | Viewed by 2824

Abstract

Diffuse infiltrating low-grade glioma (LGG) is classified as WHO grade 2 astrocytoma with isocitrate dehydrogenase (IDH) mutation and oligodendroglioma with IDH1 mutation and 1p/19q codeletion. Despite their better prognosis compared with glioblastoma, LGGs invariably recur, leading to disability and premature death. There is [...] Read more.

Diffuse infiltrating low-grade glioma (LGG) is classified as WHO grade 2 astrocytoma with isocitrate dehydrogenase (IDH) mutation and oligodendroglioma with IDH1 mutation and 1p/19q codeletion. Despite their better prognosis compared with glioblastoma, LGGs invariably recur, leading to disability and premature death. There is an unmet need to discover new therapeutics for LGG, which necessitates preclinical models that closely resemble the human disease. Basic scientific efforts in the field of neuro-oncology are mostly focused on high-grade glioma, due to the ease of maintaining rapidly growing cell cultures and highly reproducible murine tumors. Development of preclinical models of LGG, on the other hand, has been difficult due to the slow-growing nature of these tumors as well as challenges involved in recapitulating the widespread genomic and epigenomic effects of IDH mutation. The most recent WHO classification of CNS tumors emphasizes the importance of the role of IDH mutation in the classification of gliomas, yet there are relatively few IDH-mutant preclinical models available. Here, we review the in vitro and in vivo preclinical models of LGG and discuss the mechanistic challenges involved in generating such models and potential strategies to overcome these hurdles. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

16 pages, 524 KiB

Open AccessReview

Novel Therapeutic Approaches in Neoplastic Meningitis

by Atulya Aman Khosla, Shreya Saxena, Ahmad Ozair, Vyshak Alva Venur, David M. Peereboom and Manmeet S. Ahluwalia

Cancers 2023, 15(1), 119; https://doi.org/10.3390/cancers15010119 - 25 Dec 2022

Cited by 5 | Viewed by 2844

Abstract

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with [...] Read more.

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with a poor prognosis. The current management paradigm entails a multimodal approach focused on palliation with surgery, radiation, and chemotherapy, which may be administered systemically or directly into the cerebrospinal fluid (CSF). This review focuses on novel therapeutic approaches, including targeted and immunotherapeutic agents under investigation, that have shown promise in NM arising from solid tumors. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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17 pages, 1352 KiB

Open AccessReview

Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

by Valentina Bova, Alessia Filippone, Giovanna Casili, Marika Lanza, Michela Campolo, Anna Paola Capra, Alberto Repici, Lelio Crupi, Gianmarco Motta, Cristina Colarossi, Giulia Chisari, Salvatore Cuzzocrea, Emanuela Esposito and Irene Paterniti

Cancers 2022, 14(16), 4032; https://doi.org/10.3390/cancers14164032 - 20 Aug 2022

Cited by 10 | Viewed by 3068

Abstract

Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its [...] Read more.

Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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14 pages, 713 KiB

Open AccessReview

Updates on Molecular Targeted Therapies for Intraparenchymal CNS Metastases

by Akanksha Sharma, Lauren Singer and Priya Kumthekar

Cancers 2022, 14(1), 17; https://doi.org/10.3390/cancers14010017 - 21 Dec 2021

Cited by 4 | Viewed by 3487

Abstract

Central nervous system (CNS) metastases can occur in a high percentage of systemic cancer patients and is a major cause of morbidity and mortality in these patients. Almost any histology can find its way to the brain, but lung, breast, and melanoma are [...] Read more.

Central nervous system (CNS) metastases can occur in a high percentage of systemic cancer patients and is a major cause of morbidity and mortality in these patients. Almost any histology can find its way to the brain, but lung, breast, and melanoma are the most common pathologies seen in the CNS from metastatic disease. Identification of many key targets in the tumorigenesis pathway has been crucial to the development of a number of drugs that have demonstrated successful penetration of the blood–brain, blood–cerebrospinal fluid, and blood–tumor barriers. Targeted therapy and immunotherapy have dramatically revolutionized the field with treatment options that can provide successful and durable control of even CNS disease. In this review, we discuss major targets with successful treatment options as demonstrated in clinical trials. These include tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates. We also provide an update on the state of the field and highlight key upcoming trials. Patient-specific molecular information combined with novel therapeutic approaches and new agents has demonstrated and continues to promise significant progress in the management of patients with CNS metastases. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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41 pages, 2493 KiB

Open AccessReview

Therapeutic Targets in Diffuse Midline Gliomas—An Emerging Landscape

by Elisha Hayden, Holly Holliday, Rebecca Lehmann, Aaminah Khan, Maria Tsoli, Benjamin S. Rayner and David S. Ziegler

Cancers 2021, 13(24), 6251; https://doi.org/10.3390/cancers13246251 - 13 Dec 2021

Cited by 18 | Viewed by 5347

Abstract

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a [...] Read more.

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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29 pages, 1878 KiB

Open AccessReview

Molecular Classification and Therapeutic Targets in Ependymoma

by Thomas Larrew, Brian Fabian Saway, Stephen R. Lowe and Adriana Olar

Cancers 2021, 13(24), 6218; https://doi.org/10.3390/cancers13246218 - 10 Dec 2021

Cited by 25 | Viewed by 6591

Abstract

Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize behavior, prognosis, and possible targeted therapies. The current, updated molecular classification of ependymoma consists of ten distinct subgroups spread evenly among the [...] Read more.

Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize behavior, prognosis, and possible targeted therapies. The current, updated molecular classification of ependymoma consists of ten distinct subgroups spread evenly among the spinal, infratentorial, and supratentorial compartments, each with its own distinct clinical and molecular characteristics. In this review, the history, histopathology, standard of care, prognosis, oncogenic drivers, and hypothesized molecular targets for all subgroups of ependymoma are explored. This review emphasizes that despite the varied behavior of the ependymoma subgroups, it remains clear that research must be performed to further elucidate molecular targets for these tumors. Although not all ependymoma subgroups are oncologically aggressive, development of targeted therapies is essential, particularly for cases where surgical resection is not an option without causing significant morbidity. The development of molecular therapies must rely on building upon our current understanding of ependymoma oncogenesis, as well as cultivating transfer of knowledge based on malignancies with similar genomic alterations. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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21 pages, 1072 KiB

Open AccessReview

Targeted Therapies for the Neurofibromatoses

by Lauren D. Sanchez, Ashley Bui and Laura J. Klesse

Cancers 2021, 13(23), 6032; https://doi.org/10.3390/cancers13236032 - 30 Nov 2021

Cited by 17 | Viewed by 3817

Abstract

Over the past several years, management of the tumors associated with the neurofibromatoses has been recognized to often require approaches that are distinct from their spontaneous counterparts. Focus has shifted to therapy aimed at minimizing symptoms given the risks of persistent, multiple tumors [...] Read more.

Over the past several years, management of the tumors associated with the neurofibromatoses has been recognized to often require approaches that are distinct from their spontaneous counterparts. Focus has shifted to therapy aimed at minimizing symptoms given the risks of persistent, multiple tumors and new tumor growth. In this review, we will highlight the translation of preclinical data to therapeutic trials for patients with neurofibromatosis, particularly neurofibromatosis type 1 and neurofibromatosis type 2. Successful inhibition of MEK for patients with neurofibromatosis type 1 and progressive optic pathway gliomas or plexiform neurofibromas has been a significant advancement in patient care. Similar success for the malignant NF1 tumors, such as high-grade gliomas and malignant peripheral nerve sheath tumors, has not yet been achieved; nor has significant progress been made for patients with either neurofibromatosis type 2 or schwannomatosis, although efforts are ongoing. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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15 pages, 317 KiB

Open AccessFeature PaperReview

Update on Novel Therapeutics for Primary CNS Lymphoma

by Lauren R. Schaff and Christian Grommes

Cancers 2021, 13(21), 5372; https://doi.org/10.3390/cancers13215372 - 26 Oct 2021

Cited by 19 | Viewed by 4959

Abstract

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma isolated to the central nervous system or vitreoretinal space. Standard treatment consists of cytotoxic methotrexate-based chemotherapy, with or without radiation. Despite high rates of response, relapse is common, highlighting the need for novel [...] Read more.

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma isolated to the central nervous system or vitreoretinal space. Standard treatment consists of cytotoxic methotrexate-based chemotherapy, with or without radiation. Despite high rates of response, relapse is common, highlighting the need for novel therapeutic approaches. Recent advances in the understanding of PCNSL have elucidated mechanisms of pathogenesis and resistance including activation of the B-cell receptor and mammalian target of rapamycin pathways. Novel treatment strategies such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3 kinase (PI3K) inhibitors, and immunomodulatory drugs are promising. Increasingly, evidence suggests immune evasion plays a role in PCNSL pathogenesis and several immunotherapeutic strategies including checkpoint inhibition and targeted chimeric antigen receptor T (CAR-T) cells are under investigation. This review provides a discussion on the challenges in development of targeted therapeutic strategies, an update on recent treatment advances, and offers a look toward ongoing clinical studies. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

23 pages, 1477 KiB

Open AccessReview

Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma

by Kirit Singh, Kelly M. Hotchkiss, Kisha K. Patel, Daniel S. Wilkinson, Aditya A. Mohan, Sarah L. Cook and John H. Sampson

Cancers 2021, 13(21), 5367; https://doi.org/10.3390/cancers13215367 - 26 Oct 2021

Cited by 15 | Viewed by 5582

Abstract

Glioblastoma is an immunologically ‘cold’ tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at [...] Read more.

Glioblastoma is an immunologically ‘cold’ tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood–brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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