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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 -
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 -
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 -
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 -
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 -
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 -
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 -
Journal of Neuro-oncology Sep 2023Despite aggressive management consisting of surgery, radiation therapy (RT), and systemic therapy given alone or in combination, a significant proportion of patients... (Review)
Review
Despite aggressive management consisting of surgery, radiation therapy (RT), and systemic therapy given alone or in combination, a significant proportion of patients with brain tumors will experience tumor recurrence. For these patients, no standard of care exists and management of either primary or metastatic recurrent tumors remains challenging.Advances in imaging and RT technology have enabled more precise tumor localization and dose delivery, leading to a reduction in the volume of health brain tissue exposed to high radiation doses. Radiation techniques have evolved from three-dimensional (3-D) conformal RT to the development of sophisticated techniques, including intensity modulated radiation therapy (IMRT), volumetric arc therapy (VMAT), and stereotactic techniques, either stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT). Several studies have suggested that a second course of RT is a feasible treatment option in patients with a recurrent tumor; however, survival benefit and treatment related toxicity of reirradiation, given alone or in combination with other focal or systemic therapies, remain a controversial issue.We provide a critical overview of the current clinical status and technical challenges of reirradiation in patients with both recurrent primary brain tumors, such as gliomas, ependymomas, medulloblastomas, and meningiomas, and brain metastases. Relevant clinical questions such as the appropriate radiation technique and patient selection, the optimal radiation dose and fractionation, tolerance of the brain to a second course of RT, and the risk of adverse radiation effects have been critically discussed.
Topics: Humans; Re-Irradiation; Neoplasm Recurrence, Local; Brain Neoplasms; Radiotherapy, Conformal; Radiosurgery; Cerebellar Neoplasms
PubMed: 37624529
DOI: 10.1007/s11060-023-04407-2 -
Brain : a Journal of Neurology May 2021Brain metastases are the most common type of brain tumours, harbouring an immune microenvironment that can in principle be targeted via immunotherapy. Elucidating some... (Review)
Review
Brain metastases are the most common type of brain tumours, harbouring an immune microenvironment that can in principle be targeted via immunotherapy. Elucidating some of the immunological intricacies of brain metastases has opened a therapeutic window to explore the potential of immune checkpoint inhibitors in this globally lethal disease. Multiple lines of evidence suggest that tumour cells hijack the immune regulatory mechanisms in the brain for the benefit of their own survival and progression. Nonetheless, the role of the immune checkpoint in the complex interplays between cancers cells and T cells and in conferring resistance to therapy remains under investigation. Meanwhile, early phase trials with immune checkpoint inhibitors have reported clinical benefit in patients with brain metastases from melanoma and non-small cell lung cancer. In this review, we explore the workings of the immune system in the brain, the immunology of brain metastases, and the current status of immune checkpoint inhibitors in the treatment of brain metastases.
Topics: Brain; Brain Neoplasms; Humans; Immune Checkpoint Inhibitors; Neoplasm Metastasis; Tumor Escape
PubMed: 33893488
DOI: 10.1093/brain/awab012 -
Clinical & Experimental Metastasis Oct 2017Metabolic adaptations permit tumor cells to metastasize to and thrive in the brain. Brain metastases continue to present clinical challenges due to rising incidence and... (Review)
Review
Metabolic adaptations permit tumor cells to metastasize to and thrive in the brain. Brain metastases continue to present clinical challenges due to rising incidence and resistance to current treatments. Therefore, elucidating altered metabolic pathways in brain metastases may provide new therapeutic targets for the treatment of aggressive disease. Due to the high demand for glucose in the brain, increased glycolytic activity is favored for energy production. Primary tumors that undergo Warburg-like metabolic reprogramming become suited to growth in the brain microenvironment. Indeed, elevated metabolism is a predictor of metastasis in many cancer subtypes. Specifically, metabolic alterations are seen in primary tumors that are associated with the formation of brain metastases, namely breast cancer, lung cancer, and melanoma. Because of this selective pressure, inhibitors of key metabolic factors may reduce tumor cell viability, thus exploiting metabolic pathways for cancer therapeutics. This review summarizes the metabolic advantages and vulnerabilities of brain metastases.
Topics: Brain Neoplasms; Humans; Neoplasm Metastasis
PubMed: 29063238
DOI: 10.1007/s10585-017-9864-8