scholarly journals Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

2019 ◽  
Vol 20 (6) ◽  
pp. 1280 ◽  
Author(s):  
Malcolm Lim ◽  
Simon Puttick ◽  
Zachary Houston ◽  
Kristofer Thurecht ◽  
Priyakshi Kalita-de Croft ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tyrosine Kinases ◽  
Focused Ultrasound ◽  
Resistance Mechanisms ◽  
Therapeutic Strategies ◽  
Drug Uptake ◽  
Physiological Factors ◽  
Delivery Strategies ◽  
The Brain ◽  
New Strategies

Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery.

Monitoring of 57Co-bleomycin delivery to brain metastases and their tumors of origin

1987 ◽  
Vol 67 (4) ◽  
pp. 506-510 ◽  
Author(s):  
Dov Front ◽  
Einat Even-Sapir ◽  
Galina Iosilevsky ◽  
Ora Israel ◽  
Alex Frenkel ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Lung Tumor ◽  
Single Photon ◽  
Photon Emission ◽  
Lung Tumors ◽  
Drug Uptake ◽  
Content Type ◽  
Significant Difference ◽  
The Difference ◽  
The Brain

✓ The concentration of cobalt-57 (57Co)-labeled bleomycin delivered to three brain metastases and to their tumors of origin in the lungs was measured using a single-photon emission computerized tomography technique. In two brain metastases the 57Co-bleomycin concentration measured at different times after the intravenous injection was significantly lower than that in the originating lung tumors (p < 0.01 and p < 0.001). In these two patients, the tumor cumulative concentration (TCC) of drug in the brain neoplasm compared to the lung carcinoma was 12.92 versus 15.12 and 10.30 versus 19.74 µg/cc/min. In the third patient there was no significant difference in drug concentration between the tumor in the brain and in the lung (TCC 16.02 vs. 15.09 µg/cc/min). There was a significant difference in the drug TCC between the three brain metastases: the difference between the lowest and highest concentrations was more than 50% (10.3 vs. 16.02 µg/cc/min). When the concentration in the tumor over time (CT(t)) of the 57Co-bleomycin was compared in the brain and lung tumors, a good correlation was found in each of the three cases (r = 0.93, 0.99, and 0.97). This suggests that the difference in drug uptake between brain metastases and their originating lung tumor is a quantitative rather than a qualitative phenomenon. The results show that the amount of drug to which brain metastases are exposed varies and may be very low in some tumors; therefore, effectiveness of drug delivery may play a role in the nonresponsiveness of brain metastases to treatment.

scholarly journals Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2014
Author(s):  
Rinie Bajracharya ◽  
Alayna C. Caruso ◽  
Laura J. Vella ◽  
Rebecca M. Nisbet
Keyword(s):  
Focused Ultrasound ◽  
Neurological Diseases ◽  
Drug Efficacy ◽  
Brain Parenchyma ◽  
Treatment Modalities ◽  
Critical Determinant ◽  
The Central Nervous System ◽  
Antibody Delivery ◽  
The Brain ◽  
New Strategies

For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood–brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such poses a major obstacle that must be overcome for therapeutics to enter the brain. Monoclonal antibodies have emerged as one of the best-selling treatment modalities available in the pharmaceutical market owing to their high target specificity. However, it has been estimated that only 0.1% of peripherally administered antibodies can cross the BBB, contributing to the low success rate of immunotherapy seen in clinical trials for the treatment of neurological diseases. The development of new strategies for antibody delivery across the BBB is thereby crucial to improve immunotherapeutic efficacy. Here, we discuss the current strategies that have been employed to enhance antibody delivery across the BBB. These include (i) focused ultrasound in combination with microbubbles, (ii) engineered bi-specific antibodies, and (iii) nanoparticles. Furthermore, we discuss emerging strategies such as extracellular vesicles with BBB-crossing properties and vectored antibody genes capable of being encapsulated within a BBB delivery vehicle.

Long-term management of patients with multiple brain metastases after shaped beam radiosurgery

2004 ◽  
pp. 406-412
Author(s):  
Paul Okunieff ◽  
Michael C. Schell ◽  
Russell Ruo ◽  
E. Ronald Hale ◽  
Walter G. O'Dell ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tumor Control ◽  
Content Type ◽  
Negative Results ◽  
Multiple Metastases ◽  
Extracranial Disease ◽  
Successful Control ◽  
The Brain

✓ The role of radiosurgery in the treatment of patients with advanced-stage metastatic disease is currently under debate. Previous randomized studies have not consistently supported the use of radiosurgery to treat patients with numbers of brain metastases. In negative-results studies, however, intracranial tumor control was high but extracranial disease progressed; thus, patient survival was not greatly affected, although neurocognitive function was generally maintained until death. Because the future promises improved systemic (extracranial) therapy, the successful control of brain disease is that much more crucial. Thus, for selected patients with multiple metastases to the brain who remain in good neurological condition, aggressive lesion-targeting radiosurgery should be very useful. Although a major limitation to success of this therapy is the lack of control of extracranial disease in most patients, it is clear that well-designed, aggressive treatment substantially decreases the progression of brain metastases and also improves neurocognitive survival. The authors present the management and a methodology for rational treatment of a patient with breast cancer who has harbored 24 brain metastases during a 3-year period.

Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 247-254 ◽  
Author(s):  
Jason Sheehan ◽  
Douglas Kondziolka ◽  
John Flickinger ◽  
L. Dade Lunsford
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Content Type ◽  
The Brain ◽  
Fine Print

Object. Lung carcinoma is the leading cause of death from cancer. More than 50% of those with small cell lung cancer develop a brain metastasis. Corticosteroid agents, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, median survival for patients with small cell lung carcinoma metastasis is approximately 4 to 5 months after cranial irradiation. In this study the authors examine the efficacy of gamma knife surgery for treating recurrent small cell lung carcinoma metastases to the brain following tumor growth in patients who have previously undergone radiation therapy, and they evaluate factors affecting survival. Methods. A retrospective review of 27 patients (47 recurrent small cell lung cancer brain metastases) undergoing radiosurgery was performed. Clinical and radiographic data obtained during a 14-year treatment period were collected. Multivariate analysis was utilized to determine significant prognostic factors influencing survival. The overall median survival was 18 months after the diagnosis of brain metastases. In multivariate analysis, factors significantly affecting survival included: 1) tumor volume (p = 0.0042); 2) preoperative Karnofsky Performance Scale score (p = 0.0035); and 3) time between initial lung cancer diagnosis and development of brain metastasis (p = 0.0127). Postradiosurgical imaging of the brain metastases revealed that 62% decreased, 19% remained stable, and 19% eventually increased in size. One patient later underwent a craniotomy and tumor resection for a tumor refractory to radiosurgery and radiation therapy. In three patients new brain metastases were demonstrating on follow-up imaging. Conclusions. Stereotactic radiosurgery for recurrent small cell lung carcinoma metastases provided effective local tumor control in the majority of patients. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can extend survival.

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p &lt; 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values &lt; 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

scholarly journals Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Danielle Weber-Adrian ◽  
Rikke Hahn Kofoed ◽  
Joseph Silburt ◽  
Zeinab Noroozian ◽  
Kairavi Shah ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Intravenous Injection ◽  
Viral Vectors ◽  
Focused Ultrasound ◽  
Fluorescent Protein ◽  
Gfp Expression ◽  
Peripheral Organs ◽  
Neuronal Expression ◽  
Green Fluorescent ◽  
The Brain

AbstractNon-surgical gene delivery to the brain can be achieved following intravenous injection of viral vectors coupled with transcranial MRI-guided focused ultrasound (MRIgFUS) to temporarily and locally permeabilize the blood–brain barrier. Vector and promoter selection can provide neuronal expression in the brain, while limiting biodistribution and expression in peripheral organs. To date, the biodistribution of adeno-associated viruses (AAVs) within peripheral organs had not been quantified following intravenous injection and MRIgFUS delivery to the brain. We evaluated the quantity of viral DNA from the serotypes AAV9, AAV6, and a mosaic AAV1&2, expressing green fluorescent protein (GFP) under the neuron-specific synapsin promoter (syn). AAVs were administered intravenously during MRIgFUS targeting to the striatum and hippocampus in mice. The syn promoter led to undetectable levels of GFP expression in peripheral organs. In the liver, the biodistribution of AAV9 and AAV1&2 was 12.9- and 4.4-fold higher, respectively, compared to AAV6. The percentage of GFP-positive neurons in the FUS-targeted areas of the brain was comparable for AAV6-syn-GFP and AAV1&2-syn-GFP. In summary, MRIgFUS-mediated gene delivery with AAV6-syn-GFP had lower off-target biodistribution in the liver compared to AAV9 and AAV1&2, while providing neuronal GFP expression in the striatum and hippocampus.

scholarly journals Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6071
Author(s):  
Suzanne Gascon ◽  
Jessica Jann ◽  
Chloé Langlois-Blais ◽  
Mélanie Plourde ◽  
Christine Lavoie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factors ◽  
Signaling Pathways ◽  
Brain Structures ◽  
Therapeutic Strategies ◽  
Native Proteins ◽  
Receptor Sites ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

scholarly journals BSCI-20. THERAPEUTIC TARGETING OF HLA-G IN BRAIN METASTASES

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i5-i5
Author(s):  
Sheila Singh ◽  
Blessing Bassey-Archibong ◽  
Nikoo Aghaei ◽  
Agata Kieliszek ◽  
Chitra Venugopal ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Systemic Disease ◽  
Human Leukocyte ◽  
Genetic Profile ◽  
Whole Brain Radiation ◽  
Metastatic Cells ◽  
Metastatic Process ◽  
Xenograft Models ◽  
Sphere Formation ◽  
The Brain

Abstract Brain metastases (BM) are the most common brain tumor in adults, with an incidence ten times greater than that of primary brain tumors. The most common sources of BM in adult cancer patients include cancers of the lung, breast and melanoma, which together account for almost 80% of all BM. Current clinical modalities for BM include surgery, whole brain radiation therapy and stereotactic radiosurgery but these therapies still offer limited efficacy and reduced survival of only months in treated patients, emphasizing the need for novel BM research approaches and better therapeutic strategies. Our laboratory recently discovered that stem-like cells exist in patient-derived BM from lung, breast and melanoma cancers, which we termed “brain metastasis-initiating cells” or BMICs. Through clinically relevant human-mouse xenograft models established with these patient-derived BMICs, we captured lung, breast and melanoma BMICs at pre-metastasis – a key stage where circulating metastatic cells extravasate and initially seed the brain, prior to organization into micro-metastatic foci. Transcriptome analysis of pre-metastatic BMICs revealed a unique genetic profile and several genes commonly up-regulated among lung, breast and melanoma BM, including the non-classical human leukocyte class I antigen-G (HLA-G). Loss of HLA-G in lung, breast and melanoma BMICs using two HLA-G specific shRNAs attenuated sphere formation, migratory and tumor initiating abilities of lung, breast and melanoma BMICs compared to control BMICs. HLA-G knockdown also resulted in reduced phospho(p)-STAT3 expression in patient-derived BMICs suggesting a potential cooperative role between HLA-G and pSTAT3 in BM. Since HLA-G is highly expressed at the cell surface in control tumors, ongoing experiments are focused on developing HLA-G specific chimeric antigen receptor -T cells (CAR-Ts) and determining their efficacy in targeting lung-, breast- and melanoma-BM as blocking the brain metastatic process will markedly extend patient survival and ultimately transform a fatal systemic disease into a more treatable one.

TAMI-01. BRAIN METASTASES: CURRENT LITERATURE REVIEW

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi198-vi198
Author(s):  
Ruchi Raval ◽  
Aadi Pandya ◽  
Jaspreet Behl ◽  
Sumul Raval
Keyword(s):  
Literature Review ◽  
Brain Metastases ◽  
Current Literature ◽  
Anticoagulation Therapy ◽  
Signs And Symptoms ◽  
The Body ◽  
Definitive Treatment ◽  
Cognitive Changes ◽  
Cancer Breast ◽  
The Brain

Abstract PURPOSE As more information is gathered about brain metastases, it still remains that the current prognosis of brain metastases is very poor. Due to this, it is imperative that physicians are aware of the most important components regarding brain metastases. This literature review will encompass the most current literature in order to highlight the most crucial information. METHODS All mentioned studies and literature reviews cited in the paper were obtained through various sites, and were published between 1996 and 2017. The main components that were required from the papers reviewed included where in the body the brain metastases originated from, where in the brain they tended to spread to, what the signs and symptoms typical of patients with brain metastases are, and what the options are in terms of treatment. RESULTS Using the results from a variety of studies performed within the past three decades, it is apparent that brain metastases most commonly originate from, in order of increasing frequency, lung cancer, breast cancer, melanoma, and colorectal cancer. In addition, it is reaffirmed that the magnetic resonance imaging (MRI) is the best diagnostic tool to be used when dealing with brain metastases. The most frequent signs and symptoms of a brain metastases include cognitive changes, headaches, weakness, and seizures. Finally, supportive treatment includes use of corticosteroids, antiepileptic drugs (AEDs), and anticoagulation therapy. Definitive treatment for brain metastases varies based on size, location, and prevalence in the brain, but the most effective options include chemotherapy, radiation therapy, and surgery. CONCLUSIONS The study’s results confirm the need for more research to be done regarding brain metastases, and better options to increase the survival of patients.

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