%0 Journal Article
%T Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
%A Christina S. F. Wong
%A Dai Fukumura
%A Dan G. Duda
%A David P. Kodack
%A Gino B. Ferraro
%A Isabelle Kirst
%A Mark Badeaux
%A Rakesh K. Jain
%A Ram C. Shankaraiah
%A Vasileios Askoxylakis
%J Archive of "NPJ Breast Cancer".
%D 2019
%R 10.1038/s41523-018-0100-8
%X Effects of macitentan on the efficacy of T-DM1 against HER2-positive breast cancer tumors in the brain microenvironment. a Mouse survival in nude mice with BT474-Gluc brain tumors treated with i) control vehicle, T-DM1 (5£¿mg/kg, i.v. weekly), macitentan (50£¿mg/kg p.o. daily) or their combination (N£¿=£¿18-21). b Western blots were performed in BT474-Gluc tumors, collected 48£¿h after treatment (blot samples were derived from the same experiment and were processed in parallel). c Cell apoptosis was determined in BT474-Gluc brain metastases after quantification of ApopTag, 5 days after treatment with control vehicle, T-DM1 (1£¿¡Á£¿5£¿mg/kg), or T-DM1 (1£¿¡Á£¿5£¿mg/kg)£¿+£¿macitentan (5£¿¡Á£¿50£¿mg/kg) (N£¿=£¿5-9). Error bars are standard deviation. d Representative images of BT474-Gluc tumors in the brain after staining for ApopTag. Scale bar£¿=£¿0.1£¿mm. e Relative activity of Gaussia luciferase in the media of organotypic brain slice cultures of BT474-Gluc cells following treatment with T-DM1 alone or in combination with macitentan. Gluc levels from treated cells were normalized to Day 0 for each treatment. Error bars are standard deviation (N£¿=£¿5¨C7). f Western blots were performed in BT474-Gluc tumors growing in the brain or the mammary fat pad (MFP), and in MDA-MD-361-Gluc brain tumors. HER3 was used as control, since it has been previously established that the brain microenvironment increases HER3 expression6 g, h. Western blots were performed in BT474-Gluc brain tumors, collected 48£¿h after treatment with T-DM1£¿+£¿macitentan (T-DM1£¿+£¿mac. short) and at the endpoint of the study (T-DM1£¿+£¿mac. long). Tumors from mice treated with unspecific IgG were collected and used as control. i Schematic of brain-stroma mediated protection to the HER2-targeted ADC T-DM1. Direct contact of reactive astrocytes and brain endothelial cells with HER2-amplified breast cancer cells can reduce the activity of ado-trastuzumab emtansine (T-DM1) through an endothelin-pathway-mediated mechanism. Dual endothelin receptor inhibition with macitentan increases T-DM1 induced apoptosis and enhances the activity of the ADC in the brain microenvironmen
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333771/