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Immunomodulatory therapies, including immune checkpoint inhibitors, have drastically changed outcomes for certain cancer types over the last decade. Gliomas are among the cancers that have seem limited benefit from these agents, with most trials yielding negative results. The unique composition of the glioma immune microenvironment is among the culprits for this lack of efficacy. In recent years, several efforts have been made to improve understanding of the glioma immune microenvironment, aiming to pave the way for novel therapeutic interventions. In this review, we discuss some of the main components of the glioma immune microenvironment, including macrophages, myeloid-derived suppressor cells, neutrophils and microglial cells, as well as lymphocytes. We then provide a comprehensive overview of novel immunomodulatory agents that are currently in clinical development, namely oncolytic viruses, vaccines, cell-based therapies such as CAR-T cells and CAR-NK cells as well as antibodies and peptides., (© 2024. The Author(s).)

Purpose of Review: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive form of lymphoma that can involve the brain, spinal cord, leptomeninges and eyes. PCNSL prognosis continues to be poor, with 5-year survival rates of 30-40%. Therapeutic options are especially limited for relapsed/refractory (r/r) PCNSL. In recent years, studies shed light on the pathogenesis and oncogenic pathways driving PCNSL, leading to the development of novel therapeutics. In this review, we discuss the evidence supporting these novel agents and present ongoing clinical studies., Recent Findings: Key oncogenic drivers of PCNSL include activation of the NFkB pathway, cell cycle dysregulation, somatic hypermutation and immune evasion, leading to the investigation of targeted therapeutics and immunotherapeutics to inhibit these pathways. Such approaches include BTK inhibitors, mTOR/PI3K inhibitors, immunomodulatory agents (IMIDs), immune checkpoint inhibitors and CD19-based CAR T-cells. The therapeutic repertoire for PCNSL is rapidly evolving, and a multi-modality approach including intensive chemotherapy regimens and novel therapies will likely be utilized in the future., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Telomerase, crucial for maintaining telomere length, is an attractive target for cancer therapy due to its role in cellular immortality. Despite three decades of research efforts, no small-molecule telomerase inhibitors have been clinically approved, highlighting the extensive challenges in developing effective telomerase-based therapeutics. This review examines conventional and emerging methods to measure telomerase activity and discusses existing inhibitors, including oligonucleotides and small molecules. Furthermore, this review highlights recent breakthroughs in structural studies of telomerase using cryo-electron microscopy, which can facilitate improved structure-based drug design. Altogether, advancements in structural methodologies and high-throughput screening offer promising prospects for telomerase-based cancer therapeutic development., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNA Leu (TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines. We therefore aim to characterize velcrins as novel therapeutic agents in glioblastoma., Materials and Methods: PDE3A and SLFN12 expression levels were measured in glioblastoma cell lines, the Cancer Genome Atlas (TCGA) tumor samples, and tumor neurospheres. Velcrin-treated cells were assayed for viability, induction of apoptosis, cell cycle phases, and global changes in translation. Transcriptional profiling of the cells was obtained. Xenograft-harboring mice treated with velcrins were also monitored for survival., Results: We identified several velcrin-sensitive glioblastoma cell lines and 4 velcrin-sensitive glioblastoma patient-derived models. We determined that BAY 2666605 crosses the blood-brain barrier and elicits full tumor regression in an orthotopic xenograft model of GB1 cells. We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models., Conclusions: Velcrins have antitumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents., Competing Interests: P.Y.W.: Research Support: Agios, Astra Zeneca/Medimmune, Beigene, Celgene, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, VBI Vaccines. Advisory Board: Agios, Astra Zeneca, Bayer, Boston Pharmaceuticals, CNS Pharmaceuticals, Elevate Bio Immunomic Therapeutics, Imvax, Karyopharm, Merck, Novartis, Nuvation Bio, Vascular Biogenics, VBI Vaccines, Voyager, QED, Celularity, Sapience. J.G.D.: consults for Microsoft Research, Abata Therapeutics, Servier, Maze Therapeutics, BioNTech, Sangamo, and Pfizer; consults for and has equity in Tango Therapeutics; serves as a paid scientific advisor to the Laboratory for Genomics Research, funded in part by GSK; receives funding support from the Functional Genomics Consortium: Abbvie, Bristol Myers Squibb, Janssen, Merck, and Vir Biotechnology. M.M. is the scientific advisory board chair of Isabl; consults for Bayer, DelveBio, and Interline; is an inventor of patents licensed to LabCorp and Bayer; and receives research funding from Bayer and Janssen. M.M. and H.G. receive an inventor’s share of license revenue as part of their employment for certain patent filings, including US-2016-0016913 and US-2018-0235961, which relate to aspects of the work described in this manuscript. The co-owners of these patent filings are The Broad Institute, Inc., Dana-Farber Cancer Institute, Inc., and Bayer Pharma A.G., A.D.C, and H.G. also receive research funding from Bayer. A.D.C consults for KaryoVerse. K.L.L.: Research Support: BMS; Consulting: BMS, Travera, Integragen Equity: Travera., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations., (© 2024. The Author(s).)

Background: Glioblastoma is one of the most lethal forms of cancer, with 5-year survival rates of only 6%. Glioblastoma-targeted therapeutics have been challenging to develop due to significant inter- and intra-tumoral heterogeneity. Telomerase reverse transcriptase gene (TERT) promoter mutations are the most common known clonal oncogenic mutations in glioblastoma. Telomerase is therefore considered to be a promising therapeutic target against this tumor. However, an important limitation of this strategy is that cell death does not occur immediately after telomerase ablation, but rather after several cell divisions required to reach critically short telomeres. We, therefore, hypothesize that telomerase inhibition would only be effective in glioblastomas with low tumor burden., Methods: We used CRISPR interference to knock down TERT expression in TERT promoter-mutant glioblastoma cell lines and patient-derived models. We then measured viability using serial proliferation assays. We also assessed for features of telomere crisis by measuring telomere length and chromatin bridge formation. Finally, we used a doxycycline-inducible CRISPR interference system to knock down TERT expression in vivo early and late in tumor development., Results: Upon TERT inactivation, glioblastoma cells lose their proliferative ability over time and exhibit telomere shortening and chromatin bridge formation. In vivo, survival is only prolonged when TERT knockdown is induced shortly after tumor implantation, but not when the tumor burden is high., Conclusions: Our results support the idea that telomerase inhibition would be most effective at treating glioblastomas with low tumor burden, for example in the adjuvant setting after surgical debulking and chemoradiation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Glioblastoma is a malignant primary brain tumor that affects approximately 250,000 new patients per year worldwide. It is among the most difficult cancers to treat, and 5-year survival rates remain low. Standard therapies for glioblastoma include surgical resection, radiation therapy and systemic chemotherapy., Areas Covered: We conducted a search of the literature on therapeutic options for glioblastoma on Pubmed. We also searched abstracts from the American Society of Clinical Oncology, Society for Neuro-Oncology, European Association of Neuro-Oncology and American Association for Cancer Research. We also searched the U.S. National Library of Medicine clinical trials database. We discuss therapeutic options for newly diagnosed glioblastoma, mainly temozolomide, lomustine and tumor treating fields (TTF). Lastly, we discuss therapeutics for recurrent glioblastomas and agents under investigation in clinical trials., Expert Opinion: Enrollment in clinical trials is encouraged for both newly diagnosed and recurrent glioblastoma patients. The standard post-operative treatment for newly diagnosed glioblastoma patients is a combination of radiotherapy and temozolomide. TTF devices can be used in conjunction with temozolomide. Available standard therapies for recurrent glioblastoma include nitrosureas, bevacizumab and temozolomide rechallenge, as well as TTF devices. Agents that are being evaluated in clinical trials include novel targeted therapies, novel chemotherapies, and immunotherapies.

Glioblastoma is the most common primary malignant brain tumor in adults and it continues to have a dismal prognosis. The development of targeted therapeutics has been particularly challenging, in part due to a limited number of oncogenic mutations and significant intra-tumoral heterogeneity. TERT promoter mutations were first discovered in melanoma and later found to be present in up to 80% of glioblastoma samples. They are also frequent clonal alterations in this tumor. TERT promoter mutations are one of the mechanisms for telomerase reactivation, providing cancers with cellular immortality. Telomerase is a reverse transcriptase ribonucleoprotein complex that maintains telomere length in cells with high proliferative ability. In this article, we present genomic and pre-clinical data that support telomerase as a potential "Achilles' heel" for glioblastoma. We also summarize prior experience with anti-telomerase agents and potential new approaches to tackle this target., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune checkpoint inhibitors enhance immune recognition of tumors by interfering with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD1) pathways. In the past decade, these agents brought significant improvements to the prognostic outlook of patients with metastatic cancers. Recent data from retrospective analyses and a few prospective studies suggest that checkpoint inhibitors have activity against brain metastases from melanoma and nonsmall cell lung cancer, as single agents or in combination with radiotherapy. Some studies reported intracranial response rates that were comparable with systemic ones. In this review, we provide a comprehensive summary of clinical data supporting the use of anti-CTLA4 and anti-PD1 agents in brain metastases. We also touch upon specific considerations on the assessment of intracranial responses in patients and immunotherapy-specific toxicities. We conclude that a subset of patients with brain metastases benefit from the addition of checkpoint inhibitors to standard of care therapeutic modalities, including radiotherapy and surgery., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Gliomas are the most common primary malignant brain tumor in adults. The traditional classification of gliomas has been based on histologic features and tumor grade. The advent of sophisticated molecular diagnostic techniques has led to a deeper understanding of genomic drivers implicated in gliomagenesis, some of which have important prognostic implications. These advances have led to an extensive revision of the World Health Organization classification of diffuse gliomas to include molecular markers such as isocitrate dehydrogenase mutation, 1p/19q codeletion, and histone mutations as integral components of brain tumor classification. Here, we report a comprehensive analysis of molecular prognostic factors for patients with gliomas, including those mentioned above, but also extending to others such as telomerase reverse transcriptase promoter mutations, O6-methylguanine-DNA methyltransferase promoter methylation, glioma cytosine-phosphate-guanine island methylator phenotype DNA methylation, and epidermal growth factor receptor alterations.

Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples ( n  = 9) and metastatic extracranial post-treatment autopsy samples ( n  = 3). We identified "truncal" genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as NF1 ( n  = 3), TP53 ( n  = 4) and EGFR ( n  = 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the TERT promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM., Competing Interests: Dr. Batchelor has consulted for Merck, NXDC and Amgen. Dr. Brastianos has consulted for Merck, Genentech-Roche, Angiochem and Lilly.

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.

TLS (translocated in liposarcoma), also known as FUS (fused in sarcoma), is an RNA/DNA-binding protein that plays regulatory roles in transcription, pre-mRNA splicing and mRNA transport. Mutations in TLS are responsible for familial amyotrophic lateral sclerosis (ALS) type 6. Furthermore, TLS-containing intracellular inclusions are found in polyglutamine diseases, sporadic ALS, non-SOD1 familial ALS and a subset of frontotemporal lobar degeneration, indicating a pathological significance of TLS in a wide variety of neurodegenerative diseases. Here, we identified TLS domains that determine intracellular localization of the murine TLS. Among them, PY-NLS located in the C-terminus is a strong determinant of intracellular localization as well as splicing regulation of an E1A-derived minigene. Disruption of PY-NLS promoted the formation of cytoplasmic granules that were partially overlapped with stress granules and P-bodies. Some of the ALS-linked mutations altered both intracellular localization and splicing regulation of TLS, while most mutations alone did not affect splicing regulation. However, phospho-mimetic substitution of Ser505 (or Ser513 in human) could enhance the effects of ALS mutations, highlighting interplay between post-translational modification and ALS-linked mutations. These results demonstrate that ALS-linked mutations can variably cause loss of nuclear functions of TLS depending on the degree of impairment in nuclear localization.

Primary brain tumors are a major cause of cancer mortality in the United States. Therapy for gliomas, the most common type of primary brain tumors, remains suboptimal. The development of improved therapeutics will require greater knowledge of the biology of gliomas at both the genomic and transcriptional levels. We have previously reported whole genome profiling of chromosome copy number alterations (CNA) in gliomas, and now present our findings on how those changes may affect transcription of genes that may be involved in tumor induction and progression. By calculating correlation values of mRNA expression versus DNA copy number average in a moving window around a given RNA probe set, biologically relevant information can be gained that is obscured by the analysis of a single data type. Correlation coefficients ranged from -0.6 to 0.7, highly significant when compared with previous studies. Most correlated genes are located on chromosomes 1, 7, 9, 10, 13, 14, 19, 20, and 22, chromosomes known to have genomic alterations in gliomas. Additionally, we were able to identify CNAs whose gene expression correlation suggests possible epigenetic regulation. This analysis revealed a number of interesting candidates such as CXCL12, PTER, and LRRN6C, among others. The results have been verified using real-time PCR and methylation sequencing assays. These data will further help differentiate genes involved in the induction and/or maintenance of the tumorigenic process from those that are mere passenger mutations, thereby enriching for a population of potentially new therapeutic molecular targets.