title: Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.
abstract: Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+ <PC3 <HT29. In these HER2-positive tumors, nab-paclitaxel was equal to or better than polysorbate-based docetaxel in tumors with medium to high SPARC levels (PC3 and HT29), but not in MDA-MB-231/HER2+ tumors with low SPARC expression. These results demonstrated that the relative efficacy of nab-paclitaxel was significantly higher compared with polysorbate-based docetaxel in HER2-negative tumors (three of three) and in HER2-positive tumors with high levels of SPARC. HER2 and SPARC expression may be useful biomarkers in determining antitumor effectiveness for taxanes.
authors.affiliation: Abraxis BioScience, LLC, Los Angeles, California 90025-1506, USA. ndesai@abraxisbio.com
authors.forename: Neil P
authors.initials: NP
authors.lastname: Desai
authors.forename: Vuong
authors.initials: V
authors.lastname: Trieu
authors.forename: Larn Yuan
authors.initials: LY
authors.lastname: Hwang
authors.forename: Rujin
authors.initials: R
authors.lastname: Wu
authors.forename: Patrick
authors.initials: P
authors.lastname: Soon-Shiong
authors.forename: William J
authors.initials: WJ
authors.lastname: Gradishar