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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 -
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 -
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 -
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 -
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 -
Brain Research Bulletin May 2023Tremendous success using CAR T therapy in hematological malignancies has garnered significant interest in developing such treatments for solid tumors, including brain... (Review)
Review
Tremendous success using CAR T therapy in hematological malignancies has garnered significant interest in developing such treatments for solid tumors, including brain tumors. This success, however, has yet to be mirrored in solid organ neoplasms. CAR T function has shown limited efficacy against brain tumors due to several factors including the immunosuppressive tumor microenvironment, blood-brain barrier, and tumor-antigen heterogeneity. Despite these considerations, CAR T-cell therapy has the potential to be implemented as a treatment modality for brain tumors. Here, we review adult and pediatric brain tumors, including glioblastoma, diffuse midline gliomas, and medulloblastomas that continue to portend a grim prognosis. We describe insights gained from different preclinical models using CAR T therapy against various brain tumors and results gathered from ongoing clinical trials. Furthermore, we outline the challenges limiting CAR T therapy success against brain tumors and summarize advancements made to overcome these obstacles.
Topics: Child; Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Brain Neoplasms; Immunotherapy, Adoptive; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 36841424
DOI: 10.1016/j.brainresbull.2023.02.014 -
Cancer Letters Jun 2015Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and... (Review)
Review
Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM poses several unique challenges to currently available treatments for the disease. For example, GBM cells have the propensity to aggressively infiltrate/invade into the normal brain tissues and along the vascular tracks, which prevents complete resection of all malignant cells and limits the effect of localized radiotherapy while sparing normal tissue. Although anti-angiogenic treatment exerts anti-edematic effect in GBM, unfortunately, tumors progress with acquired increased invasiveness. Therefore, it is an important task to gain a deeper understanding of the intrinsic and post-treatment invasive phenotypes of GBM in hopes that the gained knowledge would lead to novel GBM treatments that are more effective and less toxic. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs. The review will also discuss several approaches to cancer therapies potentially altering GBM invasiveness.
Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Neoplasm Invasiveness
PubMed: 25796440
DOI: 10.1016/j.canlet.2015.03.015 -
Neurobiology of Disease Nov 2020Clinical studies have shown that treating many primary brain tumors is challenging due in part to the lack of safe and effective compounds that cross the blood brain... (Review)
Review
Clinical studies have shown that treating many primary brain tumors is challenging due in part to the lack of safe and effective compounds that cross the blood brain barrier (BBB) (Tan et al., 2018). However, if we were to imagine that we have ideal BBB penetrant compounds that target brain tumor cells selectively, recent studies suggest that those compounds may still not be effective due to the heterogenous nature of the tumors. In other words, there are many subsets of cells within a brain tumor, and compounds that target all those different populations are needed. This is a considerable challenge. Targeting of the cell-of-origin of these brain tumors is equally important. And yet another impediment we face is that brain tumor cells-of-origin may be protean and are able to differentiate into other cell types to drive recurrence. Therefore, an ideal BBB-penetrant compound targeting a cell-of-origin in a brain tumor may be ineffective due to the cell's ability to differentiate into another resistant cell type. One possible means of combating the plastic nature of these cells is targeting epigenetic pathways used by the cells to differentiate into other cell types along with standard treatment regimens. We summarize here some of the epigenetic pathways that have been shown to be active in three different primary brain tumors, glioblastoma (GBM), medulloblastoma (MB), and diffuse intrinsic pontine glioma (DIPG). We also compare recent single-cell RNA sequencing analyses of these tumors in order to identify common epigenetic pathways to treat the respective cells-of-origin for these tumors. Lastly, we discuss possible combination therapies that may be generalizable for treating these and other brain tumors using multi-omics approaches. While our focus on these three tumor types is not exhaustive and certainly other brain tumors can have similar mechanisms, there has been significant recent evidence linking epigenetics, plasticity, and intratumor heterogeneity in these tumors.
Topics: Brain Neoplasms; Cell Differentiation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans
PubMed: 32877743
DOI: 10.1016/j.nbd.2020.105060