scholarly journals Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

Stem Cells ◽  
2015 ◽  
Vol 33 (10) ◽  
pp. 2985-2994 ◽  
Author(s):  
Deepak Kanojia ◽  
Irina V. Balyasnikova ◽  
Ramin A. Morshed ◽  
Richard T. Frank ◽  
Dou Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells ◽  
Preclinical Model ◽  
Breast Cancer Brain Metastases

scholarly journals Human Neural Stem Cells Can Target and Deliver Therapeutic Genes to Breast Cancer Brain Metastases

2009 ◽  
Vol 17 (3) ◽  
pp. 570-575 ◽  
Author(s):  
Kyeung Min Joo ◽  
In H Park ◽  
Ji Y Shin ◽  
Juyoun Jin ◽  
Bong Gu Kang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells ◽  
Human Neural Stem Cells ◽  
Breast Cancer Brain Metastases ◽  
Therapeutic Genes

scholarly journals Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer

2021 ◽  
Vol 119 (1) ◽  
pp. e2112491119
Author(s):  
Alex Cordero ◽  
Matthew D. Ramsey ◽  
Deepak Kanojia ◽  
Jawad Fares ◽  
Edgar Petrosyan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Breast Cancer Patients ◽  
Human Neural Stem Cells ◽  
Breast Cancer Brain Metastases

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood–brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

scholarly journals SCIDOT-22. INTRACEREBROVENTRICULAR DELIVERY OF TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELLS FOR TREATMENT OF BRAIN METASTASES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi276-vi276
Author(s):  
Wulin Jiang ◽  
Alison Mercer-Smith ◽  
Juli Bago ◽  
Simon Khagi ◽  
Carey Anders ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells ◽  
Tumor Homing ◽  
Migration Assays ◽  
Induced Neural Stem Cells ◽  
First Time ◽  
The Brain

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) and breast cancer are the most common cancers that metastasize to the brain. New therapies are needed to target and eradicate metastases. We have developed genetically-engineered induced neural stem cells (hiNSCs) derived from human fibroblasts that selectively home to tumors and release the cytotoxic protein TRAIL. Building on these results, we explored the efficacy of hiNSC therapy delivered via intracerebroventricular (ICV) injections for the treatment of metastatic foci in the brain for the first time. METHODS We performed in vitro efficacy and migration assays in conjunction with in vivo studies to determine the migration, persistence, and efficacy of therapeutic hiNSCs against H460 NSCLC and triple-negative breast cancer MB231-Br tumors in the brain. Following the establishment of tumors in the brains of nude mice, hiNSCs were injected directly into the tumor or the ventricle contralateral to the tumor. The migration and persistence of hiNSCs were investigated by following the bioluminescence of the hiNSCs. The therapeutic efficacy of the hiNSCs was determined by following the bioluminescence of the tumor. RESULTS/ CONCLUSION Co-culture results demonstrated that hiNSC therapy reduced the viability of H460 and MB231-Br up to 75% and 99.8% respectively compared to non-treated controls. In vitro migration assays showed significant directional migration toward both lung and breast cancer cells within 4 days. ICV-administered hiNSC serial imaging shows that cells persisted for >1 week in the brain. Fluorescent analysis of tissue sections showed that hiNSCs co-localized with lateral and contralateral tumors within 7 days. Using H460 and MB231-Br models, kinetic tracking of intracranial tumor volumes showed intratumoral or ICV-injected therapeutic hiNSCs suppressed the growth rate of brain tumors by 31-fold and 3-fold, respectively. This work demonstrates for the first time that we can effectively deliver personalized cytotoxic tumor-homing cells through the ventricles to target brain metastases.

scholarly journals BMET-40NANO PLATFORM FOR DYNAMIC IN VIVO TRACKING OF NEURAL STEM CELLS TO BRAIN METASTASES OF BREAST CANCER

2015 ◽  
Vol 17 (suppl 5) ◽  
pp. v53.5-v54
Author(s):  
Dou Yu ◽  
Shih-Hsun Cheng ◽  
Hsiu-Ming Tsai ◽  
Deepak Kanojia ◽  
Lara Leoni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells

scholarly journals EXTH-07. TUMOR-HOMING INDUCED NEURAL STEM CELLS SECRETING A CYTOTOXIC PAYLOAD AS AN ADJUVANT TREATMENT FOR NON-SMALL CELL LUNG CANCER BRAIN METASTASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii88-ii88
Author(s):  
Alison Mercer-Smith ◽  
Wulin Jiang ◽  
Alain Valdivia ◽  
Juli Bago ◽  
Scott Floyd ◽  
...  
Keyword(s):  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells ◽  
Adjuvant Treatment ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tumor Homing ◽  
Induced Neural Stem Cells

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases. METHODS To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation. RESULTS/CONCLUSION Following ICV infusion, hiNSCs persisted in the brain for > 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes > 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases

2019 ◽  
Vol 144 (3) ◽  
pp. 583-589 ◽  
Author(s):  
Nicholas B. Figura ◽  
Thrisha K. Potluri ◽  
Homan Mohammadi ◽  
Daniel E. Oliver ◽  
John A. Arrington ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Hormone Receptor ◽  
Stereotactic Radiation ◽  
Hormone Receptor Positive ◽  
Breast Cancer Brain Metastases ◽  
Positive Breast Cancer

Breast cancer brain metastases: Molecular subtype, treatment and survival

2016 ◽  
Vol 36 (4) ◽  
pp. 133-141 ◽  
Author(s):  
Jennifer A. Crozier ◽  
Lauren F. Cornell ◽  
Bhupendra Rawal ◽  
Edith A. Perez
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Molecular Subtype ◽  
Breast Cancer Brain Metastases

scholarly journals MicroRNAs and Extracellular Vesicles as Distinctive Biomarkers of Precocious and Advanced Stages of Breast Cancer Brain Metastases Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5214
Author(s):  
Inês Figueira ◽  
Joana Godinho-Pereira ◽  
Sofia Galego ◽  
Joana Maia ◽  
János Haskó ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Brain Metastases ◽  
Extracellular Vesicles ◽  
Triple Negative ◽  
Survival Rates ◽  
Brain Parenchyma ◽  
Advanced Stages ◽  
Breast Cancer Brain Metastases

Triple negative breast cancer presents higher mortality and poorer survival rates than other breast cancer (BC) types, due to the proneness to brain metastases formation, which are usually diagnosed at advanced stages. Therefore, the discovery of BC brain metastases (BCBM) biomarkers appears pivotal for a timely intervention. With this work, we aimed to disclose microRNAs (miRNAs) and extracellular vesicles (EVs) in the circulation as biomarkers of BCBM formation. Using a BCBM animal model, we analyzed EVs in plasma by nanoparticle tracking analysis and ascertained their blood-brain barrier (BBB) origin by flow cytometry. We further evaluated circulating miRNAs by RT-qPCR and their brain expression by in situ hybridization. In parallel, a cellular model of BCBM formation, combining triple negative BC cells and BBB endothelial cells, was used to differentiate the origin of biomarkers. Established metastases were associated with an increased content of circulating EVs, particularly of BBB origin. Interestingly, deregulated miRNAs in the circulation were observed prior to BCBM detection, and their brain origin was suggested by matching alterations in brain parenchyma. In vitro studies indicated that miR-194-5p and miR-205-5p are expressed and released by BC cells, endothelial cells and during their interaction. These results highlight miRNAs and EVs as biomarkers of BCBM in early and advanced stages, respectively.

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