title: Preclinical investigation of nanoparticle albumin-bound paclitaxel as a potential treatment for adrenocortical cancer.
abstract: BACKGROUND
  Traditional drug discovery methods have a limited role in rare cancers. We hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC), a rare and lethal cancer. SPARC (secreted protein acidic rich in cysteine) is an albumin-binding matrix-associated protein that is proposed to act as a mechanism for the increased efficacy of a nanoparticle albumin-bound preparation of the antimicrotubular drug Paclitaxel (nab-paclitaxel).
  
  
  METHODS
  The transcriptomes of 19 ACC tumors and 4 normal adrenal glands were profiled on Affymetrix U133 Plus2 expression microarrays to identify genes representing potential therapeutic targets. Immunohistochemical analysis for target proteins was performed on 10 ACC, 6 benign adenomas, and 1 normal adrenal gland. Agents known to inhibit selected targets were tested in comparison with mitotane in the 2 ACC cell lines (H295R and SW-13) in vitro and in mouse xenografts.
  
  
  RESULTS
  SPARC expression is increased in ACC samples by 1.56 ± 0.44 (μ ± SD) fold. Paclitaxel and nab-paclitaxel show 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 with mitotane concentrations of 15.9 μM and 46.4 μM. In vivo nab-paclitaxel treatment shows a greater decrease in tumor weight in both xenograft models than mitotane.
  
  
  CONCLUSIONS
  Biological insights garnered through expression profiling of ACC tumors suggest further investigation into the use of nab-paclitaxel for the treatment of ACC.
authors.affiliation: Virginia G. Piper Cancer Center, Scottsdale, AZ, USA. mdemeure@tgen.org
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Demeure
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stephan
authors.forename: Shripad
authors.initials: S
authors.lastname: Sinari
authors.forename: David
authors.initials: D
authors.lastname: Mount
authors.forename: Steven
authors.initials: S
authors.lastname: Gately
authors.forename: Paul
authors.initials: P
authors.lastname: Gonzales
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.forename: Richard
authors.initials: R
authors.lastname: Komorowski
authors.forename: Jeff
authors.initials: J
authors.lastname: Kiefer
authors.forename: Clive S
authors.initials: CS
authors.lastname: Grant
authors.forename: Haiyong
authors.initials: H
authors.lastname: Han
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bussey
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology*; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000473:pathology*; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008939:Mitotane / Q000494:pharmacology; D053758:Nanoparticles; D009368:Neoplasm Transplantation / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D008939:Mitotane; D017239:Paclitaxel