scholarly journals Systemic HER3 ligand-mimicking bioparticles cross the blood–brain barrier reducing intracranial triple-negative breast cancer growth

2022 ◽  
Author(s):  
Felix Alonso-Valenteen ◽  
Sam Sances ◽  
HongQiang Wang ◽  
Simoun Mikhael ◽  
Jessica Sims ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Blood Brain Barrier ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Induced Pluripotent Stem Cell ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Abstract Triple-negative breast cancer (TNBC) lacks selective biomarkers targeted by current clinical therapies and often metastasizes to the brain. Crossing the blood-brain barrier (BBB) and reaching intracranial tumors is a clinical challenge contributing to poor prognoses for patients. The human epidermal growth factor receptor HER3 has emerged as a biomarker of metastasis and may provide a means of therapeutically targeting TNBC. We have developed HER3-targeted biological particles (bioparticles) that exhibit systemic homing to resistant and metastatic breast tumors. Here we show that HER3 is expressed on the brain endothelium and can mediate the passage of bioparticles across the BBB and into intracranial TNBC. Our findings show that the extravasation of systemic bioparticles in mice and in human induced pluripotent stem cell-based BBB chips corresponds to HER3 levels. Furthermore, systemically delivered bioparticles carrying tumoricidal agents reduced the growth of intracranial TNBC in mice and exhibited improved therapeutic profile compared to current therapies.

scholarly journals Systemic ligand-mimicking bioparticles cross the blood-brain barrier and reduce growth of intracranial triple-negative breast cancer using the human epidermal growth factor receptor 3 (HER3) to mediate both routes

2021 ◽  
Author(s):  
Felix Alonso-Valenteen ◽  
Lali K Medina-Kauwe
Keyword(s):  
Blood Brain Barrier ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Tumors ◽  
Brain Barrier ◽  
Targeted Therapeutics ◽  
Blood Brain ◽  
Epidermal Growth ◽  
The Brain

Crossing the blood-brain barrier (BBB) and reaching intracranial tumors is a significant clinical challenge for targeted therapeutics and contributes to the poor prognosis for most patients with brain malignancies. Triple-negative breast cancer (TNBC) has a high propensity for metastasis to the brain and lacks cell surface markers that can be recognized by current targeted therapies used in the clinic, thus limiting therapeutic options. The human epidermal growth factor receptor HER3 (or ErbB3) has emerged as a biomarker of therapeutic resistance and metastasis in a growing range of tumor types and may serve as a possible therapeutic target for TNBC. Accordingly, we have developed HER3-targeted biological particles (bioparticles) that assume polyhedral capsid shapes when encapsulating nucleic acid cargo, forming nano-nucleocapsids (NNCs). The NNCs exhibit systemic homing to resistant and metastatic breast tumors, including TNBC, due to the high cell surface densities of HER3 on these tumors. Here we describe our discovery that HER3 is also prominently expressed on the brain endothelium and can mediate the passage of HER3-targeted NNCs across the BBB and into triple-negative breast tumors localized in the brain. Our findings show that HER3 is present at high levels on the vasculature (but not extravascular parenchyma) of both mouse and human adult brain specimens and associates with the extravasation of systemic HER3-targeted NNCs in mice and in a human model of the BBB (BBB chip). Furthermore, systemically delivered NNCs carrying tumoricidal agents reduced the growth of intracranial TNBC tumors in mice (representing metastatic breast tumors that have established in the brain) and exhibited improved therapeutic profile compared to current therapeutic interventions (liposomal doxorubicin) used in the clinic. This study addresses the major clinical problem of systemically delivering targeted therapeutics across the blood-brain barrier (BBB), and demonstrates a new route for not only accomplishing this but also for reaching tumors localized in the brain.

Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain

2014 ◽  
Vol 232 (3) ◽  
pp. 369-381 ◽  
Author(s):  
Hava Karsenty Avraham ◽  
Shuxian Jiang ◽  
Yigong Fu ◽  
Harikrishna Nakshatri ◽  
Haim Ovadia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Blood Brain Barrier ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Brain Barrier ◽  
Blood Brain ◽  
Angiopoietin 2

scholarly journals Targeted Therapies in Triple-Negative Breast Cancer

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 159-166 ◽  
Author(s):  
Frederik Marmé ◽  
Andreas Schneeweiss
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Chemotherapy Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Receptor Subtype

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed.

scholarly journals Systemic control of cerebral metastases in a patient with HER2-positive metastatic breast cancer. Clinical case

2019 ◽  
pp. 129-134
Author(s):  
S. F. Menshikova ◽  
M. A. Frolova ◽  
M. B. Stenina
Keyword(s):  
Breast Cancer ◽  
Central Nervous System ◽  
Nervous System ◽  
Metastatic Breast Cancer ◽  
Blood Brain Barrier ◽  
Metastatic Breast ◽  
Brain Barrier ◽  
Cns Metastases ◽  
Her2 Positive ◽  
Blood Brain

Symptomatic central nervous system (CNS) metastases are diagnosed in 10–16% of patients with metastatic breast cancer (BC). Half of all these cases are HER2-positive. At present, there are no generally accepted algorithms regarding the combination and sequence of local and systemic treatment options for these patients. According to current guidelines, different local management options remain one of the main treatment methods of brain metastases control. When local treatment is limited, patients with HER2-positive BC with СNS metastases can receive anti-HER2 therapy in combination with chemo- or hormonal therapy (for luminal tumors) or as single option. Trastuzumab poorly penetrates the blood-brain barrier, but trastuzumab-based treatment schedules increase the life expectancy in patients with HER2-positive BC with CNS metastases mainly due to control of extracranial metastases. Lapatinib, by contrast, penetrates the blood-brain barrier well, and its combination with capecitabine achieves response in heavily pretreated patients, especially in those who have central nervous system metastases as the only site of disease progression.

scholarly journals Blood-Brain Barrier Integrity and Breast Cancer Metastasis to the Brain

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Farheen Arshad ◽  
Lili Wang ◽  
Christopher Sy ◽  
Shalom Avraham ◽  
Hava Karsenty Avraham
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Brain Barrier ◽  
Treatment Modalities ◽  
Blood Brain ◽  
The Brain

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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