Abstract 2250: COX2-MMP1 pathway promotes brain metastasis by tampering with blood-brain barrier and supporting tumor initiating cells in the brain microenvironment

Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors.

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RADI-03. A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.073 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii18-iii18

Author(s):

Lauritz Miarka ◽

Catia Moteiro ◽

Celine Dalmasso ◽

Coral Fustero-Torre ◽

Natalia Yebra ◽

...

Keyword(s):

Brain Metastasis ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Unmet Need ◽

Brain Barrier ◽

Breast Adenocarcinoma ◽

Therapeutic Benefits ◽

Blood Brain ◽

The Brain

Abstract Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

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P02.01 A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance

Neuro-Oncology ◽

10.1093/neuonc/noab180.054 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii17-ii17

Author(s):

L Miarka ◽

C Monteiro ◽

C Dalmasso ◽

N Yebra ◽

C Fustero-Torre ◽

...

Keyword(s):

Brain Metastasis ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Unmet Need ◽

Brain Barrier ◽

Breast Adenocarcinoma ◽

Therapeutic Benefits ◽

Blood Brain ◽

The Brain

Abstract BACKGROUND Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. MATERIAL AND METHODS We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. RESULTS An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFκB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. CONCLUSION We identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

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The treatment of brain metastasis from breast cancer, role of blood-brain barrier disruption and early experience with trastuzumab

Therapy ◽

10.1586/14750708.3.1.97 ◽

2006 ◽

Vol 3 (1) ◽

pp. 97-112 ◽

Cited By ~ 2

Author(s):

Rose Marie Tyson ◽

Dale F Kraemer ◽

Matthew A Hunt ◽

Leslie L Muldoon ◽

Peter Orbay ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Early Experience ◽

Brain Barrier ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

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Oxidative Stress Increases the Blood Brain Barrier Permeability Resulting in Increased Incidence of Brain Metastasis in BRCA Mutation Carriers

10.21236/ada560888 ◽

2012 ◽

Author(s):

Hava Avraham

Keyword(s):

Oxidative Stress ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Brca Mutation ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Brca Mutation Carriers

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Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

Current Medicinal Chemistry ◽

10.2174/0929867324666171106163742 ◽

2018 ◽

Vol 25 (9) ◽

pp. 1073-1089 ◽

Cited By ~ 1

Author(s):

Santiago Vilar ◽

Eduardo Sobarzo-Sanchez ◽

Lourdes Santana ◽

Eugenio Uriarte

Keyword(s):

Blood Brain Barrier ◽

In Silico ◽

Passive Diffusion ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Different Types ◽

The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

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Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200128145124 ◽

2020 ◽

Vol 26 (37) ◽

pp. 4721-4737 ◽

Cited By ~ 4

Author(s):

Bhumika Kumar ◽

Mukesh Pandey ◽

Faheem H. Pottoo ◽

Faizana Fayaz ◽

Anjali Sharma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Side Effects ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Targeting ◽

Neural Cells ◽

Blood Brain ◽

The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

Current Pharmaceutical Design ◽

10.2174/1381612826666200316130128 ◽

2020 ◽

Vol 26 (13) ◽

pp. 1448-1465 ◽

Cited By ~ 1

Author(s):

Jozef Hanes ◽

Eva Dobakova ◽

Petra Majerova

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Neurodegenerative Disorders ◽

Brain Barrier ◽

Neuronal Function ◽

Brain Drug Delivery ◽

Naturally Occurring ◽

Blood Brain ◽

Traditional Approaches ◽

The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

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Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽

10.3390/pharmaceutics13060892 ◽

2021 ◽

Vol 13 (6) ◽

pp. 892

Author(s):

Elisa L. J. Moya ◽

Elodie Vandenhaute ◽

Eleonora Rizzi ◽

Marie-Christine Boucau ◽

Johan Hachani ◽

...

Keyword(s):

Drug Discovery ◽

Blood Brain Barrier ◽

Early Stage ◽

Molecular Transport ◽

Brain Barrier ◽

Blood Brain ◽

Cns Drugs ◽

The Impact ◽

The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

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Probable Causes of Alzheimer’s Disease

Sci ◽

10.3390/sci3010016 ◽

2021 ◽

Vol 3 (1) ◽

pp. 16

Author(s):

James David Adams

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lactic Acid ◽

Blood Brain Barrier ◽

Transient Receptor Potential ◽

Brain Barrier ◽

Folate Intake ◽

Blood Brain ◽

Age Related ◽

The Brain

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

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