Glioblastoma treatment slowly moves toward change: novel druggable targets and translational horizons in 2022.

INTRODUCTION: Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches. AREAS COVERED: This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations. EXPERT OPINION: GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific 'off-the-shelf' CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.

How to treat histone 3 altered gliomas: molecular landscape and therapeutic developments.

INTRODUCTION: Diffuse midline gliomas (DMG) and diffuse hemispheric glioma (DHG) are both rare tumors characterized and recognized for specific alterations of histone 3 including H3K27 (DMG) and H3G34 (DHG). Despite these tumors arising from alterations of the same gene their clinical, radiological, and molecular behaviors strongly diverge, requiring a personalized therapeutic approach. AREAS COVERED: We performed a review on Medline/PudMed aiming to search papers relative to prospective trials, retrospective studies, case series, and case reports of interest in order to investigate current knowledge toward the main clinical and molecular characteristics, radiology, and diagnosis, loco-regional and systemic treatments of these tumors. Moreover, we also evaluated the novel treatments under investigation. EXPERT OPINION: Thanks to an increased knowledge of the genomic landscape of these rare tumors, there are novels promising therapeutic targets for these malignancies. However, the majority of available trials allowed enrollment only in DMG, while few studies are focused on or allow the inclusion of DHG patients.

Beyond Imaging and Genetic Signature in Glioblastoma: Radiogenomic Holistic Approach in Neuro-Oncology.

Glioblastoma (GBM) is a malignant brain tumor exhibiting rapid and infiltrative growth, with less than 10% of patients surviving over 5 years, despite aggressive and multimodal treatments. The poor prognosis and the lack of effective pharmacological treatments are imputable to a remarkable histological and molecular heterogeneity of GBM, which has led, to date, to the failure of precision oncology and targeted therapies. Identification of molecular biomarkers is a paradigm for comprehensive and tailored treatments; nevertheless, biopsy sampling has proved to be invasive and limited. Radiogenomics is an emerging translational field of research aiming to study the correlation between radiographic signature and underlying gene expression. Although a research field still under development, not yet incorporated into routine clinical practice, it promises to be a useful non-invasive tool for future personalized/adaptive neuro-oncology. This review provides an up-to-date summary of the recent advancements in the use of magnetic resonance imaging (MRI) radiogenomics for the assessment of molecular markers of interest in GBM regarding prognosis and response to treatments, for monitoring recurrence, also providing insights into the potential efficacy of such an approach for survival prognostication. Despite a high sensitivity and specificity in almost all studies, accuracy, reproducibility and clinical value of radiomic features are the Achilles heel of this newborn tool. Looking into the future, investigators' efforts should be directed towards standardization and a disciplined approach to data collection, algorithms, and statistical analysis.

Tumor-Associated Microenvironment of Adult Gliomas: A Review.

The glioma-associated tumor microenvironment involves a multitude of different cells ranging from immune cells to endothelial, glial, and neuronal cells surrounding the primary tumor. The interactions between these cells and glioblastoma (GBM) have been deeply investigated while very little data are available on patients with lower-grade gliomas. In these tumors, it has been demonstrated that the composition of the microenvironment differs according to the isocitrate dehydrogenase status (mutated/wild type), the presence/absence of codeletion, and the expression of specific alterations including H3K27 and/or other gene mutations. In addition, mechanisms by which the tumor microenvironment sustains the growth and proliferation of glioma cells are still partially unknown. Nonetheless, a better knowledge of the tumor-associated microenvironment can be a key issue in the optic of novel therapeutic drug development.

Hypermutation as a potential predictive biomarker of immunotherapy efficacy in high-grade gliomas: a broken dream?

A high tumor mutational burden and mismatch repair deficiency are observed in 'hypermutated' high-grade gliomas (HGGs); however, the molecular characterization of this distinct subtype and whether it predicts the response to immune checkpoint inhibitors (ICIs) are largely unknown. Pembrolizumab is a valid therapeutic option for the treatment of hypermutated cancers of diverse origin, but only a few clinical trials have explored the activity of ICIs in hypermutated HGGs. HGGs appear to differ from other cancers, likely due to the prevalence of subclonal versus clonal neoantigens, which are unable to elicit an immune response with ICIs. The main aim of this review is to summarize the current knowledge on hypermutation in HGGs, focusing on the broken promises of tumor mutational burden and mismatch repair deficiency as potential biomarkers of response to ICIs.

An interesting question arising in neuro-oncology is whether a high mutational load (a condition termed 'hypermutation') can be as immunogenic in high-grade gliomas as in other solid tumors. The most recent literature has raised the question of whether hypermutated high-grade gliomas may be 'insensitive' to immunotherapy, especially in patients pretreated with temozolomide, which is the standard of care for glioma therapy. The purpose of this review is to summarize the available evidence on hypermutated gliomas and their sensitivity to immunotherapy agents.

Pharmacotherapeutic Treatment of Glioblastoma: Where Are We to Date?

The clinical management of glioblastoma (GBM) is still bereft of treatments able to significantly improve the poor prognosis of the disease. Despite the extreme clinical need for novel therapeutic drugs, only a small percentage of patients with GBM benefit from inclusion in a clinical trial. Moreover, often clinical studies do not lead to final interpretable conclusions. From the mistakes and negative results obtained in the last years, we are now able to plan a novel generation of clinical studies for patients with GBM, allowing the testing of multiple anticancer agents at the same time. This assumes critical importance, considering that, thanks to improved knowledge of altered molecular mechanisms related to the disease, we are now able to propose several potential effective compounds in patients with both newly diagnosed and recurrent GBM. Among the novel compounds assessed, the initially great enthusiasm toward trials employing immune checkpoint inhibitors (ICIs) was disappointing due to the negative results that emerged in three randomized phase III trials. However, novel biological insights into the disease suggest that immunotherapy can be a convincing and effective treatment in GBM even if ICIs failed to prolong the survival of these patients. In this regard, the most promising approach consists of engineered immune cells such as chimeric antigen receptor (CAR) T, CAR M, and CAR NK alone or in combination with other treatments. In this review, we discuss several issues related to systemic treatments in GBM patients. First, we assess critical issues toward the planning of clinical trials and the strategies employed to overcome these obstacles. We then move on to the most relevant interventional studies carried out on patients with previously untreated (newly diagnosed) GBM and those with recurrent and pretreated disease. Finally, we investigate novel immunotherapeutic approaches with special emphasis on preclinical and clinical data related to the administration of engineered immune cells in GBM.

Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance.

Glioblastoma is an aggressive tumor and is associated with a dismal prognosis. The availability of few active treatments as well as the inexorable recurrence after surgery are important hallmarks of the disease. The biological behavior of glioblastoma tumor cells reveals a very complex pattern of genomic alterations and is partially responsible for the clinical aggressiveness of this tumor. It has been observed that glioblastoma cells can recruit, manipulate and use other cells including neurons, glial cells, immune cells, and endothelial/stromal cells. The final result of this process is a very tangled net of interactions promoting glioblastoma growth and progression. Nonetheless, recent data are suggesting that the microenvironment can also be a niche in which glioblastoma cells can differentiate into glial cells losing their tumoral phenotype. Here we summarize the known interactions between micro-environment and glioblastoma cells highlighting possible therapeutic implications.

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer "orphan" entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.

Expertise is crucial to prolong survival in average risk medulloblastoma: long-term results of a retrospective study.

PURPOSE: Medulloblastoma is a rare tumor in adults and the use of adjuvant chemotherapy in average risk patients is debated. METHODS: Patients included in our study were ⩾16 years of age, had histologically confirmed medulloblastoma, and underwent adjuvant radiotherapy with or without chemotherapy. Average risk was defined according to the Chang classification. RESULTS: We included 48 average-risk patients. Median follow-up was 151.5 months (95% confidence interval, 124.5-178.5). Both progression-free survival (PFS) and overall survival (OS) were significantly influenced by adjuvant chemotherapy (PFS: hazard ratio [HR], 0.334, p = 0.05; OS: HR, 0.187, p = 0.017) and by receiving the treatment in a referral center (PFS: HR, 0.250, p = 0.008; OS: HR, 0.295, p = 0.038). CONCLUSIONS: Treating patients with average-risk medulloblastoma in a referral center improves both PFS and OS, does adding adjuvant chemotherapy.

Clinical and Molecular Features of Patients with Gliomas Harboring IDH1 Non-canonical Mutations: A Systematic Review and Meta-Analysis.

INTRODUCTION: The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH-mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear. METHODS: We performed a systematic review and meta-analysis to assess the clinical role of IDH non-canonical mutations. RESULTS: Overall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 glioma including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4-10.7%) in patients with IDH-mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference 31%, 95% CI 23-38%) and presented a significantly prolonged survival (pooled HR 0.47, 95% CI 0.28-0.81) as compared to those with IDH1 R132H mutation. CONCLUSION: Non-canonical IDH1 mutations occur in 7.9% of IDH-mutated gliomas and identify a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for improved stratification and selection of patients.

Engineered CAR-T and novel CAR-based therapies to fight the immune evasion of glioblastoma: gutta cavat lapidem.

INTRODUCTION: The field of cancer immunotherapy has achieved great advancements through the application of genetically engineered T cells with chimeric antigen receptors (CAR), that have shown exciting success in eradicating hematologic malignancies and have proved to be safe with promising early signs of antitumoral activity in the treatment of glioblastoma (GBM). AREAS COVERED: We discuss the use of CAR T cells in GBM, focusing on limitations and obstacles to advancement, mostly related to toxicities, hostile tumor microenvironment, limited CAR T cells infiltration and persistence, target antigen loss/heterogeneity and inadequate trafficking. Furthermore, we introduce the refined strategies aimed at strengthening CAR T activity and offer insights in to novel immunotherapeutic approaches, such as the potential use of CAR NK or CAR M to optimize anti-tumor effects for GBM management. EXPERT OPINION: With the progressive wide use of CAR T cell therapy, significant challenges in treating solid tumors, including central nervous system (CNS) tumors, are emerging, highlighting early disease relapse and cancer cell resistance issues, owing to hostile immunosuppressive microenvironment and tumor antigen heterogeneity. In addition to CAR T cells, there is great interest in utilizing other types of CAR-based therapies, such as CAR natural killer (CAR NK) or CAR macrophages (CAR M) cells for CNS tumors.

Discovering the Molecular Landscape of Meningioma: The Struggle to Find New Therapeutic Targets.

Meningiomas are the most common primary CNS tumors. They are usually benign but can present aggressive behavior in about 20% of cases. The genetic landscape of meningioma is characterized by the presence (in about 60% of cases) or absence of NF2 mutation. Low-grade meningiomas can also present other genetic alterations, particularly affecting SMO, TRAF7, KLF4 AKT1 and PI3KCA. In higher grade meningiomas, mutations of TERT promoter and deletion of CDKN2A/B seem to have a prognostic value. Furthermore, other genetic alterations have been identified, such as BAP1, DMD and PBRM1. Different subgroups of DNA methylation appear to be correlated with prognosis. In this review, we explored the genetic landscape of meningiomas and the possible therapeutic implications.

Correction: Visani et al. miR-196B-5P and miR-200B-3P Are Differentially Expressed in Medulloblastomas of Adults and Children. Diagnostics 2020, 10, 265.

The authors wish to make the following corrections to this paper [...].

Is Molecular Tailored-Therapy Changing the Paradigm for CNS Metastases in Breast Cancer?

Breast cancer (BC) is the second most common tumour spreading to the central nervous system (CNS). The prognosis of patients with CNS metastases depends on several parameters including the molecular assessment of the disease. Although loco-regional treatment remains the best approach, systemic therapies are acquiring a role leading to remarkable long-lasting responses. The efficacy of these compounds diverges between tumours with different molecular assessments. Promising agents under investigation are drugs targeting the HER2 pathways such as tucatinib, neratinib, pyrotinib, trastuzumab deruxtecan. In addition, there are several promising agents under investigation for patients with triple-negative brain metastases (third-generation taxane, etirinotecan, sacituzumab, immune-checkpoint inhibitors) and hormone receptor-positive brain metastases (CDK 4/5, phosphoinositide-3-kinase-mammalian target of rapamycin [PI3K/mTOR] inhibitors). Also, the systemic treatment of leptomeningeal metastases, which represents a very negative prognostic site of metastases, is likely to change as several compounds are under investigation, some with interesting preliminary results. Here we performed a comprehensive review focusing on the current management of CNS metastases according to molecular subtypes, site of metastases (leptomeningeal vs brain), and systemic treatments under investigation.

Distinct MRI pattern of "pseudoresponse" in recurrent glioblastoma multiforme treated with regorafenib: Case report and literature review.

Antiangiogenic agents can induce a distinct MRI pattern in glioblastoma, characterized by a decrease in the contrast enhancement on T1-weighted images and a simultaneous hyperintensity on T2-weighted or fluid-attenuated inversion recovery images.

Glioblastoma: Emerging Treatments and Novel Trial Designs.

Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting.

IDH Inhibitors and Beyond: The Cornerstone of Targeted Glioma Treatment.

Diffuse low-grade gliomas account for approximately 20% of all primary brain tumors, they arise from glial cells and show infiltrative growth without histological features of malignancy. Mutations of the IDH1 and IDH2 genes constitute a reliable molecular signature of low-grade gliomas and are the earliest driver mutations occurring during gliomagenesis, representing a relevant biomarker with diagnostic, prognostic, and predictive value. IDH mutations induce a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate, which leads to widespread effects on cellular epigenetics and metabolism. Currently, there are no approved molecularly targeted therapies and the standard treatment for low-grade gliomas consists of radiation therapy and chemotherapy, with rising concern about treatment-related toxicities. Targeting D-2-hydroxyglutarate is considered a novel attractive therapeutic approach for low-grade gliomas and the insights from clinical trials suggest that mutant-selective IDH inhibitors are the ideal candidates, with a favorable benefit/risk ratio. A pivotal question is whether blocking IDH neomorphic activity may activate alternative oncogenetic pathways, inducing acquired resistance to IDH inhibitors. Based on this rationale, combination therapies to enhance the antitumor activity of IDH inhibitors and approaches aimed at exploiting, rather than inhibiting, the metabolism of IDH-mutant cancer cells, such as poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors, are emerging from preclinical research and clinical trials. In this review, we discuss the pivotal role of IDH mutations in gliomagenesis and the complex interactions between the genomic and epigenetic landscapes, providing an overview of how, in the last decade, therapeutic approaches for low-grade gliomas have evolved.

Liquid Biopsy in Glioblastoma Management: From Current Research to Future Perspectives.

Glioblastoma (GBM) is the most common primary tumor of the central nervous system. Arising from neuroepithelial glial cells, GBM is characterized by invasive behavior, extensive angiogenesis, and genetic heterogeneity that contributes to poor prognosis and treatment failure. Currently, there are several molecular biomarkers available to aid in diagnosis, prognosis, and predicting treatment outcomes; however, all require the biopsy of tumor tissue. Nevertheless, a tissue sample from a single location has its own limitations, including the risk related to the procedure and the difficulty of obtaining longitudinal samples to monitor treatment response and to fully capture the intratumoral heterogeneity of GBM. To date, there are no biomarkers in blood or cerebrospinal fluid for detection, follow-up, or prognostication of GBM. Liquid biopsy offers an attractive and minimally invasive solution to support different stages of GBM management, assess the molecular biology of the tumor, identify early recurrence and longitudinal genomic evolution, predict both prognosis and potential resistance to chemotherapy or radiotherapy, and allow patient selection for targeted therapies. The aim of this review is to describe the current knowledge regarding the application of liquid biopsy in glioblastoma, highlighting both benefits and obstacles to translation into clinical care. IMPLICATIONS FOR PRACTICE: To translate liquid biopsy into clinical practice, further prospective studies are required with larger cohorts to increase specificity and sensitivity. With the ever-growing interest in RNA nanotechnology, microRNAs may have a therapeutic role in brain tumors.