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Clinical Journal of Oncology Nursing Oct 2016Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Current treatment options at diagnosis are multimodal and include surgical... (Review)
Review
BACKGROUND
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Current treatment options at diagnosis are multimodal and include surgical resection, radiation, and chemotherapy. Significant advances in the understanding of the molecular pathology of GBM and associated cell signaling pathways have opened opportunities for new therapies for recurrent and newly diagnosed disease. Innovative treatments, such as tumor-treating fields (TTFields) and immunotherapy, give hope for enhanced survival.
OBJECTIVES
This article reviews the background, risks, common complications, and treatment options for GBM.
METHODS
A brief review of GBM, treatment options, and a look at new therapies that have been approved for new and recurrent disease are included in this article.
FINDINGS
Despite aggressive resection and combined modality adjuvant treatment, most GBMs recur. Treatments, such as TTFields, drugs to target molecular receptors, and immunotherapy, are promising new options.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Risk Factors
PubMed: 27668386
DOI: 10.1188/16.CJON.S1.2-8 -
Nature Reviews. Cancer Jan 2020For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the... (Review)
Review
For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumours as well as brain metastases. In this Review, we highlight the cellular and molecular components of the blood-brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumours are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood-tumour barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of molecules. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging molecular, cellular and physical strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biology approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.
Topics: Animals; Antineoplastic Agents; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Combined Modality Therapy; Drug Delivery Systems; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Precision Medicine; Tumor Microenvironment
PubMed: 31601988
DOI: 10.1038/s41568-019-0205-x -
F1000Research 2018Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some... (Review)
Review
Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some point during the course of their disease. The management of brain metastasis is rapidly evolving and the roles of local therapies such as whole-brain radiation therapy, stereotactic radiosurgery, and resection along with systemic therapies are in flux. An emphasis on the neurocognitive side effects associated with treatment has gained prominence. Novel molecular studies have demonstrated important evolutionary patterns underpinning the development of brain metastasis and leptomeningeal disease, which may be key to unlocking new therapeutic strategies. This article provides a framework for incorporating the results of recent randomized radiotherapy clinical trials into practice, expounds upon the emphasis on cognition being an important driver in therapeutic selection, describes the importance of CNS-penetrating systemic therapies, and provides an overview of the novel molecular insights that will likely set the stage for future developments in this field.
Topics: Brain Neoplasms; Disease Management; Humans; Neoplasm Metastasis; Radiosurgery; Radiotherapy; Therapeutics
PubMed: 30473769
DOI: 10.12688/f1000research.15903.1 -
International Journal of Molecular... Dec 2020Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms... (Review)
Review
Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms underlying treatment failure, the standard-of-care therapy has not changed over the last two decades, signifying a great unmet need. The challenges of treating glioblastoma are many and include inadequate drug or agent delivery across the blood-brain barrier, abundant intra- and intertumoral heterogeneity, redundant signaling pathways, and an immunosuppressive microenvironment. Here, we review the innate and adaptive molecular mechanisms underlying glioblastoma's treatment resistance, emphasizing the intrinsic challenges therapeutic interventions must overcome-namely, the blood-brain barrier, tumoral heterogeneity, and microenvironment-and the mechanisms of resistance to conventional treatments, targeted therapy, and immunotherapy.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Resistance, Neoplasm; Glioblastoma; Humans; Molecular Targeted Therapy; Tumor Microenvironment
PubMed: 33396284
DOI: 10.3390/ijms22010351 -
Nature Dec 2020Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we...
Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we introduce an in vivo barcoding strategy that is capable of determining the metastatic potential of human cancer cell lines in mouse xenografts at scale. We validated the robustness, scalability and reproducibility of the method and applied it to 500 cell lines spanning 21 types of solid tumour. We created a first-generation metastasis map (MetMap) that reveals organ-specific patterns of metastasis, enabling these patterns to be associated with clinical and genomic features. We demonstrate the utility of MetMap by investigating the molecular basis of breast cancers capable of metastasizing to the brain-a principal cause of death in patients with this type of cancer. Breast cancers capable of metastasizing to the brain showed evidence of altered lipid metabolism. Perturbation of lipid metabolism in these cells curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a resource to support metastasis research.
Topics: Animals; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Electronic Data Processing; Female; Heterografts; Humans; Lipid Metabolism; Mice; Molecular Typing; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Organ Specificity; Pilot Projects
PubMed: 33299191
DOI: 10.1038/s41586-020-2969-2 -
American Family Physician Feb 2016Primary intracranial tumors of the brain structures, including meninges, are rare with an overall five-year survival rate of 33.4%; they are collectively called primary... (Review)
Review
Primary intracranial tumors of the brain structures, including meninges, are rare with an overall five-year survival rate of 33.4%; they are collectively called primary brain tumors. Proven risk factors for these tumors include certain genetic syndromes and exposure to high-dose ionizing radiation. Primary brain tumors are classified by histopathologic criteria and immunohistochemical data. The most common symptoms of these tumors are headache and seizures. Diagnosis of a suspected brain tumor is dependent on appropriate brain imaging and histopathology. The imaging modality of choice is gadolinium-enhanced magnetic resonance imaging. There is no specific pathognomonic feature on imaging that differentiates between primary brain tumors and metastatic or nonneoplastic disease. In cases of suspected or pathologically proven metastatic disease, chest and abdomen computed tomography may be helpful, although determining the site of the primary tumor is often difficult, especially if there are no clinical clues from the history and physical examination. Using fluorodeoxyglucose positron emission tomography to search for a primary lesion is not recommended because of low specificity for differentiating a neoplasm from benign or inflammatory lesions. Treatment decisions are individualized by a multidisciplinary team based on tumor type and location, malignancy potential, and the patient's age and physical condition. Treatment often includes a combination of surgery, radiotherapy, and chemotherapy. After craniotomy, patients should be followed closely for complications, including deep venous thrombosis, pulmonary embolism, intracranial bleeding, wound infection, systemic infection, seizure, depression, worsening neurologic status, and adverse drug reaction. Hospice and palliative care should be offered when appropriate throughout treatment.
Topics: Adult; Brain; Brain Neoplasms; Combined Modality Therapy; Humans; Magnetic Resonance Imaging; Tomography, X-Ray Computed
PubMed: 26926614
DOI: No ID Found -
Cells Mar 2021Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic... (Review)
Review
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)-tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics-are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Cell Lineage; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Neoplastic Stem Cells; Phenotype; Radiation Tolerance; Tumor Microenvironment
PubMed: 33799798
DOI: 10.3390/cells10030621 -
Oncogene Jun 2023Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to... (Review)
Review
Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to therapy lies within the heterogeneity of the tumor and its associated microenvironment. The vast diversity of cell states, composition of cells, and phenotypical characteristics makes it difficult to accurately classify GBM into distinct subtypes and find effective therapies. The advancement of sequencing technologies in recent years has further corroborated the heterogeneity of GBM at the single cell level. Recent studies have only begun to elucidate the different cell states present in GBM and how they correlate with sensitivity to therapy. Furthermore, it has become clear that GBM heterogeneity not only depends on intrinsic factors but also strongly differs between new and recurrent GBM, and treatment naïve and experienced patients. Understanding and connecting the complex cellular network that underlies GBM heterogeneity will be indispensable in finding new ways to tackle this deadly disease. Here, we present an overview of the multiple layers of GBM heterogeneity and discuss novel findings in the age of single cell technologies.
Topics: Humans; Glioblastoma; Brain Neoplasms; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 37277603
DOI: 10.1038/s41388-023-02738-y -
Cell Reports Oct 2017Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA...
Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor's genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.
Topics: Brain Neoplasms; Cluster Analysis; DNA Copy Number Variations; Glioblastoma; Humans; Magnetic Resonance Imaging; RNA, Neoplasm; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 29091775
DOI: 10.1016/j.celrep.2017.10.030 -
Cancer Discovery Nov 2015Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown....
UNLABELLED
Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.
SIGNIFICANCE
Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.
Topics: Brain Neoplasms; Cluster Analysis; Disease Progression; Drug Resistance, Neoplasm; Exome; Genetic Heterogeneity; Genetic Variation; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Lymph Nodes; Molecular Targeted Therapy; Mutation; Neoplasms; Signal Transduction
PubMed: 26410082
DOI: 10.1158/2159-8290.CD-15-0369