Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent

Emilia M. Pinto, Christopher Morton, Carlos Rodriguez-Galindo, Lisa McGregor, Andrew M. Davidoff, Kimberly Mercer, Larisa V. Debelenko, Catherine Billups, Raul C. Ribeiro, Gerard P. Zambetti

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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. Conclusion: Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.

Original languageEnglish (US)
Pages (from-to)1740-1747
Number of pages8
JournalClinical Cancer Research
Volume19
Issue number7
DOIs
StatePublished - Apr 1 2013

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Topotecan
Heterografts
Adrenocortical Carcinoma
Neoplasms
Preclinical Drug Evaluations
DNA Fingerprinting
Loss of Heterozygosity
Adrenal Cortex
Gene Expression Profiling
Etoposide
Pediatric Adrenocortical Carcinoma
Doxorubicin
Cisplatin
Research Design
Animal Models
Alleles
Cell Line
Mutation
Growth
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Pinto, Emilia M. ; Morton, Christopher ; Rodriguez-Galindo, Carlos ; McGregor, Lisa ; Davidoff, Andrew M. ; Mercer, Kimberly ; Debelenko, Larisa V. ; Billups, Catherine ; Ribeiro, Raul C. ; Zambetti, Gerard P. / Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 7. pp. 1740-1747.
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abstract = "Purpose: 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. Experimental Design: 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. Conclusion: Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.",
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Pinto, EM, Morton, C, Rodriguez-Galindo, C, McGregor, L, Davidoff, AM, Mercer, K, Debelenko, LV, Billups, C, Ribeiro, RC & Zambetti, GP 2013, 'Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent', Clinical Cancer Research, vol. 19, no. 7, pp. 1740-1747. https://doi.org/10.1158/1078-0432.CCR-12-3354

Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent. / Pinto, Emilia M.; Morton, Christopher; Rodriguez-Galindo, Carlos; McGregor, Lisa; Davidoff, Andrew M.; Mercer, Kimberly; Debelenko, Larisa V.; Billups, Catherine; Ribeiro, Raul C.; Zambetti, Gerard P.

In: Clinical Cancer Research, Vol. 19, No. 7, 01.04.2013, p. 1740-1747.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent

AU - Pinto, Emilia M.

AU - Morton, Christopher

AU - Rodriguez-Galindo, Carlos

AU - McGregor, Lisa

AU - Davidoff, Andrew M.

AU - Mercer, Kimberly

AU - Debelenko, Larisa V.

AU - Billups, Catherine

AU - Ribeiro, Raul C.

AU - Zambetti, Gerard P.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Purpose: 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. Experimental Design: 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. Conclusion: Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.

AB - Purpose: 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. Experimental Design: 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. Conclusion: Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.

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