scholarly journals Brain Metastasis Treatment: The Place of Tyrosine Kinase Inhibitors and How to Facilitate Their Diffusion across the Blood–Brain Barrier

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1446
Author(s):  
Eurydice Angeli ◽  
Guilhem Bousquet
Keyword(s):  
Brain Metastases ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Blood Brain Barrier ◽  
Kinase Inhibitors ◽  
Brain Barrier ◽  
Molecular Alterations ◽  
Blood Brain ◽  
Recent Advances ◽  
Breast Cancer Brain Metastases

The incidence of brain metastases has been increasing constantly for the last 20 years, because of better control of metastases outside the brain, and the failure of most drugs to cross the blood–brain barrier at relevant pharmacological concentrations. Recent advances in the molecular biology of cancer have led to the identification of numerous molecular alterations, some of them targetable with the development of specific targeted therapies, including tyrosine kinase inhibitors. In this narrative review, we set out to describe the state-of-the-art in the use of tyrosine kinase inhibitors for the treatment of melanoma, lung cancer, and breast cancer brain metastases. We also report preclinical and clinical pharmacological data on brain exposure to tyrosine kinase inhibitors after oral administration and describe the most recent advances liable to facilitate their penetration of the blood–brain barrier at relevant concentrations and limit their physiological efflux.

scholarly journals Esophageal Gastrointestinal Stromal Tumor with Rare Intracranial Metastasis

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
José Carvalho ◽  
Margarida Teixeira ◽  
Francisco Teixeira Silva ◽  
Alexandra Esteves ◽  
Carlos Ribeiro ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Blood Brain Barrier ◽  
Kinase Inhibitors ◽  
Lung Metastases ◽  
Whole Brain Radiotherapy ◽  
Brain Barrier ◽  
Mesenchymal Tumors ◽  
Intracranial Metastasis ◽  
Brain Radiotherapy ◽  
Blood Brain

Introduction. Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors and constitute the largest group of nonepithelial digestive neoplasms. However, they do not represent more than 1% of primary digestive tumors. They commonly metastasize to the liver and peritoneum, but brain metastases are extremely rare. Clinical Case. A 76-year-old woman with a diagnosis of esophageal GIST with liver and lung metastases for 13 years, medicated with imatinib, is presented. She was brought to the emergency department after falling and due to changes in behavior and vertigo with 24 hours of evolution. On physical examination, she presented changes in behavior, dysarthria, dysmetria on the right, gait imbalance, and no motor or sensory deficits. On brain computed tomography and posteriorly on magnetic resonance, 2 lesions were observed, left frontal and right cerebellar, compatible with metastatic lesions. After contribution of neurosurgery, histology was obtained that confirmed the lesions were GIST metastases. Imatinib was maintained, and whole brain radiotherapy was performed. After 6 months, she died. Discussion. The rarity of GIST brain metastases is noteworthy, and because of that, there is not enough experience to be certain of the best treatment. Our patient lived for 13 years with excellent disease control with imatinib, but the fact that it does not cross the blood-brain barrier makes it not useful in preventing or treating brain lesions. New tyrosine kinase inhibitors that may cross the blood-brain barrier could be the answer to these cases.

scholarly journals Lipid polymeric nanoparticles modified with tight junction-modulating peptides promote afatinib delivery across a blood–brain barrier model

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Li Lo ◽  
Hua-Ching Lin ◽  
Shu-Ting Hong ◽  
Chih-Hsien Chang ◽  
Chen-Shen Wang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Polymeric Nanoparticles ◽  
Growth Factor Receptor ◽  
Brain Barrier ◽  
Polymeric Nanoparticle ◽  
Blood Brain ◽  
Blood Brain Barrier Model ◽  
Delivery Platform

Abstract Background Brain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies. Afatinib (Afa) is an orally administered irreversible ErbB family blocker approved for epidermal growth factor receptor (EGFR)-mutated NSCLC. However, the incidence of brain metastases in patients with NSCLC and EGFR mutation is high. One of the major obstacles in the treatment of brain metastases is to transport drugs across the blood–brain barrier (BBB). A lipid polymeric nanoparticle (LPN) modified with a tight junction-modulating peptide is a potential formulation to deliver therapeutics across the BBB. FD7 and CCD are short peptides that perturb the tight junctions (TJs) of the BBB. In this study, the use of LPN modified with FD7 or CCD as a delivery platform was explored to enhance Afa delivery across the BBB model of mouse brain-derived endothelial bEnd.3 cells. Results Our findings revealed that Afa/LPN-FD7 and Afa/LPN-CCD exhibited a homogeneous shape, a uniform nano-scaled particle size, and a sustained-release profile. FD7, CCD, Afa/LPN-FD7, and Afa/LPN-CCD did not cause a significant cytotoxic effect on bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD across the bEnd.3 cells enhanced the cytotoxicity of Afa on human lung adenocarcinoma PC9 cells. FD7 and CCD-modulated TJ proteins, such as claudin 5 and ZO-1, reduced transendothelial electrical resistance, and increased the permeability of paracellular markers across the bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD were also partially transported through clathrin- and caveolae-mediated transcytosis, revealing the effective activation of paracellular and transcellular pathways to facilitate Afa delivery across the BBB and cytotoxicity of Afa on PC9 cells. Conclusion TJ-modulating peptide-modified LPN could be a prospective platform for the delivery of chemotherapeutics across the BBB to the brain for the potential treatment of the BM of NSCLC.

scholarly journals TRLS-08. CNS PENETRATION AND PRELIMINARY EFFICACY OF SACUTIZUMAB GOVITECAN IN BREAST BRAIN METASTASIS AND GLIOBLASTOMA: A SURGICAL STUDY

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i10-i10 ◽  
Author(s):  
Andrew Brenner ◽  
John Floyd ◽  
Prathiba Surapaneni ◽  
Vinu Madhusudanan-Kunnuparampil ◽  
Stefano Tiziani
Keyword(s):  
Blood Brain Barrier ◽  
Standard Dose ◽  
Total Concentration ◽  
Therapeutic Benefit ◽  
Brain Barrier ◽  
Priority Review ◽  
Antibody Drug Conjugate ◽  
Blood Brain ◽  
Cns Penetration ◽  
Breast Cancer Brain Metastases

Abstract Sacituzumab govitecan (SG) is an antibody drug conjugate (ADC) that targets Trop-2 for the selective delivery of SN-38 to tumors. SG carries SN-38, a topoisomerase inhibitor active in the nanomolar range for most cells (including TNBC and GBM) and freely cross the blood brain barrier. SN-38 is conjugated to SG by a linker designated CL2A which is sensitive to acidic conditions. SG has since been granted priority review designation by the FDA, with approval anticipated for triple negative breast cancer. Brain metastases is a significant concern in this patient population, but whether this agent is able to target the CNS through the blood brain barrier is unknown. Based upon the characteristics of this specific ADC, including the use of a pH labile linker and a payload with good CNS penetration, it is our specific hypothesis that the SG can achieve intratumoral concentrations of SN-38 sufficient to achieve therapeutic benefit in patients with neoplastic involvement of the brain. We further hypothesize that while total concentration of SN-38 will correlate with expression of trop2, free SN-38 will correlate more strongly with intratumoral hypoxia. To address this, we are performing a non-randomized, prospective study of SG in subjects with CNS involvement and planned surgical resection. SG is given as single dose at 10mg/kg pre-operatively on Day-1. Surgery will be followed by post-operative treatment with sacituzumab govitecan given intravenously with standard dose of 10 mg/kg on day1 and day 8 of 21-day cycle, until disease progression. Approximately 20 patients, 2 cohorts of 10 patients each with GBM and breast brain tumors, will be enrolled. Tumors will be analyzed for total antibody, free SN-38, and total SN-38 (free SN-38 + Antibody-SN38) concentrations in tumor tissue. Correlations will be made to Trop2 expression and hypoxia. Interim results will be presented.

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