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Neurotherapeutics : the Journal of the... Apr 2017Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately... (Review)
Review
Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.
Topics: Adult; Brain Neoplasms; Child; Child, Preschool; Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 28374184
DOI: 10.1007/s13311-017-0524-0 -
International Journal of Molecular... Jul 2021Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for... (Review)
Review
Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway.
Topics: Brain Neoplasms; Humans; Molecular Targeted Therapy; Mutation; Neoplasm Proteins; Rare Diseases; Signal Transduction
PubMed: 34360713
DOI: 10.3390/ijms22157949 -
MedGenMed : Medscape General Medicine Dec 2004Pilomyxoid astrocytoma (PMA) is a recently described type of brain tumor. PMA shares similar features with pilocytic astrocytoma (PA), the most common central nervous... (Review)
Review
Pilomyxoid astrocytoma (PMA) is a recently described type of brain tumor. PMA shares similar features with pilocytic astrocytoma (PA), the most common central nervous system (CNS) tumor in the pediatric population, yet displays subtle histologic differences. Previous studies have shown PMA to behave more aggressively than PA, with shorter progression-free and overall survival as well as a higher rate of recurrence and CNS dissemination. These findings suggest that PMA may be a unique and distinct neoplasm. This review summarizes the histologic, clinical, and radiographic characteristics of PMA. In addition, the current treatment options and research endeavors involving this disease are described. Increased recognition of PMA within the medical community has the potential to affect the treatment and prognosis of pediatric low-grade astrocytomas.
Topics: Astrocytoma; Brain; Brain Neoplasms; Humans; Radiography
PubMed: 15775869
DOI: No ID Found -
Cancer Letters May 2020High-grade glioma (HGG), and particularly Glioblastoma (GBM), can exhibit pronounced intratumoral heterogeneity that confounds clinical diagnosis and management. While... (Review)
Review
High-grade glioma (HGG), and particularly Glioblastoma (GBM), can exhibit pronounced intratumoral heterogeneity that confounds clinical diagnosis and management. While conventional contrast-enhanced MRI lacks the capability to resolve this heterogeneity, advanced MRI techniques and PET imaging offer a spectrum of physiologic and biophysical image features to improve the specificity of imaging diagnoses. Published studies have shown how integrating these advanced techniques can help better define histologically distinct targets for surgical and radiation treatment planning, and help evaluate the regional heterogeneity of tumor recurrence and response assessment following standard adjuvant therapy. Application of texture analysis and machine learning (ML) algorithms has also enabled the emerging field of radiogenomics, which can spatially resolve the regional and genetically distinct subpopulations that coexist within a single GBM tumor. This review focuses on the latest advances in neuro-oncologic imaging and their clinical applications for the assessment of intratumoral heterogeneity.
Topics: Algorithms; Brain Neoplasms; Contrast Media; Glioma; Humans; Machine Learning; Magnetic Resonance Imaging; Neoplasm Recurrence, Local; Positron-Emission Tomography; Therapy, Computer-Assisted
PubMed: 32112907
DOI: 10.1016/j.canlet.2020.02.025 -
Frontiers in Immunology 2019Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and... (Review)
Review
Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.
Topics: Blood-Brain Barrier; Brain Neoplasms; Humans; Neoplasm Metastasis; Tumor Escape; Tumor Microenvironment
PubMed: 31396225
DOI: 10.3389/fimmu.2019.01713 -
Pharmaceutical Patent Analyst May 2014This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following... (Review)
Review
This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood-brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application.
Topics: Antineoplastic Agents; Brain; Brain Neoplasms; Humans; Neoplasm Metastasis; Patents as Topic
PubMed: 24998288
DOI: 10.4155/ppa.14.19 -
Nature Medicine Jul 2020Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid...
Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging.
Topics: Biomarkers, Tumor; Brain Neoplasms; Cell-Free Nucleic Acids; CpG Islands; DNA Methylation; DNA, Neoplasm; Epigenome; Female; Gene Expression Regulation, Neoplastic; Humans; Male
PubMed: 32572265
DOI: 10.1038/s41591-020-0932-2 -
CNS Oncology Sep 2022Antibody-drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part...
Antibody-drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to poor macromolecule penetration across the blood-brain tumor barrier. Trastuzumab deruxtecan (T-DXd), a high-payload antibody-drug conjugate, was recently found to improve progression-free survival in HER2+ breast cancer patients versus prior-generation trastuzumab emtansine, prompting us to evaluate CNS activity in a woman with brain-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent, previously-irradiated lesions were biopsy-proven to represent treatment effect. Subsequent recurrence occurred upon treatment holiday; partial response was observed with rechallenge. This case suggests T-DXd is active in HER2+ breast cancer brain metastases and supports further prospective evaluation.
Topics: Antibodies, Monoclonal, Humanized; Brain Neoplasms; Breast Neoplasms; Camptothecin; Female; Humans; Immunoconjugates; Receptor, ErbB-2; Trastuzumab
PubMed: 35674041
DOI: 10.2217/cns-2022-0010 -
CNS Oncology 2015Glioblastoma (GBM) is the most common adult primary brain neoplasm. Despite advances in treatment, GBM continues to be associated with considerable morbidity and... (Review)
Review
Glioblastoma (GBM) is the most common adult primary brain neoplasm. Despite advances in treatment, GBM continues to be associated with considerable morbidity and mortality as compared with other malignancies. Standard treatment for GBM results in survival of 12.9 months (95% CI: 12.3-13.7 months) with a median progression-free survival of 7.2 months (95% CI: 6.4-8.2 months) in a modern GBM cohort. These aggressive tumors recur and treatment for recurrent GBM continues to have very poor outcomes. Prior to the use of bevacizumab, monoclonal antibody to VEGF, 6-month progression-free survival in clinical trials for recurrent GBM ranged from 9 to 15%. Trials utilizing bevacizumab and its subsequent US FDA approval have given more hope to recurrent GBM and this concise review discusses bevacizumab in recurrent GBM. This review focuses on time-to-event outcomes (overall survival, progression-free survival and 6-month progression-free survival) in clinical trials utilizing bevacizumab for the treatment of recurrent GBM. For this review, we have chosen to focus primarily on Phase II clinical trials that have been published and available in the literature (PubMed). While we focused primarily on time-to-event variables, toxicity and safety of bevacizumab is very important and this agent can be associated with serious life-threatening toxicities. We have included a general section of toxicities but for a more lengthy review please see the excellent study by Odia and colleagues.
Topics: Angiogenesis Inhibitors; Bevacizumab; Brain Neoplasms; Clinical Trials as Topic; Female; Glioblastoma; Humans; Male
PubMed: 25906439
DOI: 10.2217/cns.15.8 -
Oncotarget May 2016Although brain tumors have been known tremendously over the past decade, there are still many problems to be solved. The etiology of brain tumors is not well understood... (Review)
Review
Although brain tumors have been known tremendously over the past decade, there are still many problems to be solved. The etiology of brain tumors is not well understood and the treatment remains modest. There is in great need to develop a suitable brain tumor models that faithfully mirror the etiology of human brain neoplasm and subsequently get more efficient therapeutic approaches for these disorders. In this review, we described the current status of animal models of brain tumors and analyzed their advantages and disadvantages. Additionally, prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), a versatile genome editing technology for investigating the functions of target genes, and its application were also introduced in our present work. We firstly proposed that brain tumor modeling could be well established via CRISPR/Cas9 techniques. And CRISPR/Cas9-mediated brain tumor modeling was likely to be more suitable for figuring out the pathogenesis of brain tumors, as CRISPR/Cas9 platform was a simple and more efficient biological toolbox for implementing mutagenesis of oncogenes or tumor suppressors that were closely linked with brain tumors.
Topics: Animals; Biomarkers, Tumor; Brain Neoplasms; CRISPR-Associated Proteins; CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Diffusion of Innovation; Disease Models, Animal; Forecasting; Gene Editing; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Phenotype
PubMed: 26993776
DOI: 10.18632/oncotarget.8075