scholarly journals 281P Prognostic impact of immune interactions in HER2+ and triple-negative breast cancer brain metastases

2021 ◽  
Vol 32 ◽  
pp. S486-S487
Author(s):  
G. Griguolo ◽  
A. Tosi ◽  
M.V. Dieci ◽  
S. Fineberg ◽  
A. Ventura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Prognostic Impact ◽  
Breast Cancer Brain Metastases

scholarly journals BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i1-i2
Author(s):  
Shenqi Zhang ◽  
Christopher May ◽  
Anupama Shirali ◽  
Valentina Dubljevic ◽  
James Campbell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Tumor ◽  
Nucleoside Transporter ◽  
Cell Nuclei ◽  
Filter Model ◽  
Breast Cancer Brain Metastases ◽  
The Brain

Abstract An unusual lupus anti-DNA autoantibody, 3E10, has potential to be used against triple-negative breast cancer (TNBC) brain metastases. 3E10 penetrates live cell nuclei, inhibits DNA repair, and is selectively toxic to cancer cells with the PTEN and/or DNA-damage response (DDR)-deficiencies that are associated with brain metastases in TNBC. The ENT2 nucleoside transporter that 3E10 uses to cross cell membranes is highly expressed in tumors and in brain endothelial cells (BECs) at the blood-brain barrier (BBB), and 3E10 has previously delivered cargo proteins to ischemic brain in a rat stroke model. We have re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (PAT-DX1), that has increased effect on PTEN/DDR-deficient tumor cells. In the present study we tested the ability of PAT-DX1 to cross the BBB and improve outcomes in a mouse model of TNBC brain metastases. PAT-DX1 crossed from apical to basolateral chambers in an hCMEC/D3 Transwell filter model of the BBB, and penetrated the nuclei of and was toxic to the brain-seeking 231-BR subclone of MDA-MB-231 TNBC cells, which harbors a loss of PTEN compared to parental cells. Brain metastases were generated in nude mice by intracardiac injection of 1.75x105 231-BR cells engineered for expression of luciferase, as confirmed by IVIS one week after injection. Mice with brain metastases were treated by tail vein injection of control (PBS, n=7) or DX1 (20 mg/kg, n=7) 3x/week for 4 weeks. Mice were observed for behavior and weights, and brain radiance efficiency was monitored by weekly IVIS to track metastatic tumor growth. PAT-DX1 significantly suppressed growth of brain metastases based on absolute and relative radiance efficiencies in the brain, increased the median survival of the mice from 38 to 52 days (P< 0.02), and was well tolerated. These results provide proof of concept for use of a re-engineered autoantibody against brain metastases.

scholarly journals TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

2014 ◽  
Vol 146 (3) ◽  
pp. 557-566 ◽  
Author(s):  
Carey Anders ◽  
Allison M. Deal ◽  
Vandana Abramson ◽  
Minetta C. Liu ◽  
Anna M. Storniolo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Phase Ii Study ◽  
Breast Cancer Brain Metastases

scholarly journals Abstract 4055: Genomic and immune characterization of triple-negative breast cancer brain metastases

2018 ◽  
Author(s):  
Benjamin G. Vincent ◽  
Maria Sambade ◽  
Shengjie Chai ◽  
Marni B. Siegel ◽  
Luz Cuaboy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Brain Metastases

scholarly journals Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1246
Author(s):  
Marta Sanz-Álvarez ◽  
Ion Cristóbal ◽  
Melani Luque ◽  
Andrea Santos ◽  
Sandra Zazo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Molecular Target ◽  
Prognostic Impact ◽  
Breast Cancer Patients ◽  
Bet Inhibitors ◽  
Brd4 Inhibition ◽  
Bet Protein

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

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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