title: Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent.
abstract: OBJECTIVE
  Pediatric adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. Conventional chemotherapeutic agents have shown limited utility and are largely ineffective in treating children with advanced ACC. The lack of cell lines and animal models of pediatric ACC has hampered the development of new therapies. Here we report the establishment of the first pediatric ACC xenograft model and the characterization of its sensitivity to selected chemotherapeutic agents.
  
  
  METHODS
  A tumor from an 11-year-old boy with previously untreated ACC was established as a subcutaneous xenograft in immunocompromised CB17 scid(-/-) mice. The patient harbored a germline TP53 G245C mutation, and the primary tumor showed loss of heterozygosity with retention of the mutated TP53 allele. Histopathology, DNA fingerprinting, gene expression profiling, and biochemical analyses of the xenograft were conducted and compared with the primary tumor and normal adrenal cortex. The second endpoint was to assess the preliminary antitumor activity of selected chemotherapeutic agents.
  
  
  RESULTS
  The xenograft maintained the histopathologic and molecular features of the primary tumor. Screening the xenograft for drug responsiveness showed that cisplatin had a potent antitumor effect. However, etoposide, doxorubicin, and a panel of other common cancer drugs had little or no antitumor activity, with the exception of topotecan, which was found to significantly inhibit tumor growth. Consistent with these preclinical findings, topotecan as a single agent in a child with relapsed ACC resulted in disease stabilization.
  
  
  CONCLUSIONS
  Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.
authors: International Outreach Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Emilia M
authors: EM
authors: Pinto
authors: Christopher
authors: C
authors: Morton
authors: Carlos
authors: C
authors: Rodriguez-Galindo
authors: Lisa
authors: L
authors: McGregor
authors: Andrew M
authors: AM
authors: Davidoff
authors: Kimberly
authors: K
authors: Mercer
authors: Larisa V
authors: LV
authors: Debelenko
authors: Catherine
authors: C
authors: Billups
authors: Raul C
authors: RC
authors: Ribeiro
authors: Gerard P
authors: GP
authors: Zambetti
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D012008:Recurrence; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019772:Topotecan / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D019772:Topotecan