Sihem Bihorel
University of Florida, USA
Posters & Accepted Abstracts: J Cancer Sci Ther
HER2-positive breast cancer (BC) is fast-growing and more aggressive than other types of BC. Trastuzumab (TZM), an anti-HER2 receptor humanized monoclonal antibody, is used in BC in combination with paclitaxel (PAC) in a 24 h sequence treatment during the first week followed by a simultaneous administration thereafter. There is no scientific rationale for such therapeutic regimen. Here we propose to utilize a proteomics approach to optimize the sequential combination of PAC+TZM to enhance their anti-tumoral activity, and hence patients� outcome. Six therapeutic regimens were investigated in vitro on BT474 cells: A human BC cell line overexpressing HER2 receptor, including PAC and TZM alone at 50 and 100 nM, a tumor priming regimen (TPR) with PAC given 24 h prior to TZM, a reverse-TPR, a concurrent regimen and a vehicle as a control. Proteomics analysis was conducted in each regimen and several identified key signaling proteins in the PAC+TZM pathway were measured over time, including p21, p27, ERK1,2, JNK1,2, and cleaved-PARP. TPR showed more amplified proteins dynamic responses compared to others with: 1) Continuous activation of p21 and p27, both are hallmark biomarkers for the cell-cycle arrest response, and 2) down regulation of HER2 survival pathways mediated via ERK1,2 and JNK1,2. A more efficacious ADCC and a sustained apoptotic response were also observed. TPR elicits synergistic interactions in vitro. The underlying mechanisms involve increased apoptosis, cell-cycle arrest, and antibody-dependent cellular cytotoxicity. The proposed research will develop and employ a systems pharmacology model to design optimal regimens for the association (PAC+TZM) in HER2-positive BC.
Email: sihem.bihorel@cop.ufl.edu
Cancer Science & Therapy received 3968 citations as per Google Scholar report
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