Pre-clinical evidence for nab-paclitaxel efficacy in the treatment of adrenocortical cancer

Abstract

22070 Background: Adrenocortical carcinoma (ACC) is a rare and lethal cancer with an average incidence of 0.7 in 1 million. Response to current standard therapy including mitotane is approximately 22%. Expression profiling analysis of human tumors has identified potential therapeutic targets which were then tested in in vitro and in vivo systems. Methods: RNA samples from 25 ACC tumors and 4 normal adrenal glands were profiled on both the Affymetrix Human Genome U133 Plus 2 and Agilent 22K element expression arrays. Novel therapeutic targets identified were tested in comparison with mitotane in two ACC cell lines (H295R and SW-13) in vitro and in vivo in a Scid mouse xenograft system. Protein levels of selected genes were subsequently assayed by IHC of a xenograft tumor TMA. Results: Expression of SPARC (secreted protein acidic rich in cysteine), an albumin binding matrix protein involved in cell structure and cell cycle progression, is upregulated within the ACC tumor population 1.50 + 0.81 (μ+SD) and 3.54+ 2.37 (μ+SD) fold on the Affymetrix and Agilent platforms, respectively. The anti-microtubular drugs paclitaxel and nanoparticle albumin bound paclitaxel (ABRAXANE®) exhibited in vitro inhibition of H295R and SW-13 cells at IC50 concentrations of 0.33 μM and 0.0078 μM for paclitaxel and 0.35 μM and 0.0087 μM for nab-paclitaxel compared to mitotane concentrations of 15.9 μM and 46.4 μM. IHC staining of treated xenograft tumors shows no induction of MDR1 with nab-paclitaxel treatment. Conclusions: Biological insight garnered through expression profiling of ACC tumors supports the clinical investigation of nab-paclitaxel use in the treatment of ACC in which there is over-expression of SPARC. No significant financial relationships to disclose.